Methods for restoration of histamine balance

ABSTRACT

Several embodiments provided herein relate to histamine dosing regimens are and uses of such regimens in the restoration of histamine balance in subjects suffering from, for example, histapenia and/or histadelia. Several embodiments also relate to the use of histamine dosing regimens for the treatment and/or prevention of migraine headaches.

RELATED CASES

This application is a continuation of U.S. patent application Ser. No.15/341,839, filed Nov. 2, 2016, which is a continuation of U.S. patentapplication Ser. No. 14/684,174, now U.S. Pat. No. 9,511,054, filed Apr.10, 2015, which is a continuation of U.S. patent application Ser. No.14/315,206, now U.S. Pat. No. 9,023,881, filed Jun. 25, 2014, which is acontinuation in part of International Application No. PCT/US2013/046420,filed Jun. 18, 2013, which claims the benefit of U.S. ProvisionalApplication No. 61/733,630, filed Dec. 5, 2012. U.S. patent applicationSer. No. 14/315,206 also claims the benefit of U.S. ProvisionalApplication No. 61/867,966, filed on Aug. 20, 2013 and U.S. ProvisionalApplication No. 62/002,613, filed on May 23, 2014. The entire disclosureof each of the applications listed above is incorporated by referenceherein.

BACKGROUND Field

Several embodiments of the present invention relate generally to methodsfor the restoration of histamine balance. In particular, severalembodiments related restoring histamine levels to normal ranges in orderto treat various illnesses or disorders.

Description of the Related Art

Histamine, also referred to chemically as 2-(1H-imidazol-4-yl)ethanamineis composed of an imidazole ring and an amino group connected by a chainof two carbon atoms (see FIG. 1). Histamine is the decarboxylationproduct of the amino acid histidine and is associated with local immuneresponses to foreign pathogens. For example, the granules of mast cellsor white blood cells generate and/or store histamine which is releasedupon injury or exposure to allergens. Histamine also functions as aneurotransmitter and plays a role in the pathways of gastric acidsecretion in the stomach.

SUMMARY

Dysregulation or imbalances of the histamine system can be a leadingcontributor to a variety of disease states and symptoms, many of whichcan be debilitating or life-disruptive. For example, abnormally highhistamine levels can lead to excessive allergies (or hyperactiveresponses to allergens), hyperactivity, compulsive or obsessivebehavior, vertigo, inner ear pressure, depression, anxiety, panicattacks, migraine headaches, heightened emotional sensitivity and/orsuicidal tendencies. Reduced histamine levels can lead to depressedmetabolism and/or weight gain, paranoia, grandiosity, hallucinations(e.g., classic schizophrenic symptoms), tinnitus, hirsutism, visual andauditory abnormalities, anxiety and food sensitivities. The potentialcosts (both emotional and financial) of histamine imbalance, be they toan individual person or family, related to societal lost productivityand/or burdens on the medical system, are immense. In 2012 America willhave spent $200 billion in direct costs for those with Alzheimer'sDisease. Caring for people with Alzheimer's Disease is estimated to costat least $20 trillion over the next 40 years. Furthermore, the economicburden of Parkinson's disease is at least $14.4 billion a year with anestimate that the prevalence of Parkinson's disease will more thandouble by year 2040.

Several embodiments of the present invention relate to the use of agentsthat up-regulate or down-regulate expression and/or activity of one ormore histamine receptors. Histamine agonists and antagonists,naturally-occurring or synthetic, are provided in several embodiments.For example, in one embodiment, titrated histamine dosing regimens areused to restore normal histamine function. The dosing regimens areuseful, in several embodiments, for restoring histamine function inpatients having deficient or excessive levels of histamine, and can beused to treat or prevent any disorders in which histamine imbalanceplays a causative role.

Although histamine is used as the therapeutic agent in many embodiments,the invention is not limited to the administration of histamine. Forexample, therapeutic agents that mimic the effects of histamine are usedin some embodiments. Histamine agonists, antagonists, and other agentsthat interact or interfere with histamine receptors are used astherapeutic agents in several embodiments. Therapeutic agents may, forexample, provide stop the progression of symptoms, or may reduce orprevent the onset or severity of symptoms. A surprising versatile dosingregimen has been developed for the administration of histamine, or othertherapeutic agent, that relies, in several embodiments, on sequentialdosing segments. In several embodiments, each segment includes aplurality of escalating doses. For example, in one embodiment, theregimen comprises a plurality of dosing segments, each comprising aplurality of doses, wherein each segment is defined by the same volumefor every dose and the same time interval between every dose, butconcentrations of the therapeutic agent (e.g., histamine) are increasedfrom dose to dose, and each successive segment is defined by a greaterdosing volume than the previous segment and a longer time intervalbetween doses. The administration of histamine or other therapeuticagent, as used herein, includes the administration of itspharmaceutically acceptable salt (such as, for example, histaminephosphate, histamine dihydrochloride or any other histamine salt). Thus,references to the administration of histamine encompass theadministration of pharmacologically acceptable salts and forms inseveral embodiments. A histamine receptor activator includes but is notlimited to histamine (and its pharmacologically acceptable salts andother forms). Moreover, in several embodiments, adjunct therapeuticinterventions are used, either in place of, or in conjunction withadministration of histamine and/or an additional therapeutic agent. Forexample, in several embodiments, an electromagnetic device is used togenerate a magnetic field that can be focused (or applied diffusely) toa subject having imbalanced histamine levels. In several embodiments,electromagnetic energy is delivered to a subject to return histaminelevels to within normal ranges. In some embodiments, the electromagneticenergy is tailored (e.g., by frequency, wavelength, field strength,etc.) to target one or more specific histamine receptors. In severalembodiments, the use of electromagnetic devices acts synergisticallywith administration of histamine to return histamine levels to normalranges. However, as discussed above, in several embodiments, suchdevices are used independent of histamine administration (oradministration of other therapeutic agents).

Thus, in several embodiments, the invention comprises or consistsessentially of an escalating dosing regimen comprising in sequentialorder (a) a first dosing segment comprising two or more sequential dosesof a therapeutic agent (e.g., histamine) separated by one or more equaltime intervals (the “first time interval”), wherein the doses increasein histamine concentration from dose to dose while the administeredvolume of each dose stays constant; and (b) a second dosing segmentcomprising two or more sequential doses of a therapeutic agent (e.g.,histamine) separated by one or more equal time intervals (the “secondtime interval”), wherein the doses increase in concentration from doseto dose while the administered volume of each dose stays constant;wherein the volume of each dose in the second dosing segment is greaterthan the volume of each dose in the first dosing segment, and the secondtime interval is longer than the first time interval. In severalembodiments, the invention comprises a multi-variable approach forincreasing or decreasing histamine levels. The multi-variable approachis beneficial in several embodiments because physiological parameterscan be more finely-tuned. For example, cellular distribution andreceptor contact can be modulated to achieve selective activation ofcertain histamine receptors, while leaving other histamine receptorssubstantially unaffected.

In several embodiments, the invention includes administering (orinstructing the administration of) several doses of a therapeutic agent(such as histamine or a histamine salt), as described herein in variousembodiments. For example, in some embodiments, the invention includesadministering a first therapy segment that comprises or consistsessentially of (i) activating a histamine H3 receptor by administeringto a subject a first dose of a therapeutic agent (such as histamine or ahistamine salt); (ii) activating a histamine H4 receptor byadministering a second dose of the therapeutic agent; (iii) activating ahistamine H1 receptor by administering a third dose of the therapeuticagent; and (iv) activating a histamine H2 receptor by administering afourth dose of the therapeutic agent. In additional embodiments, theinvention includes administering a first therapy segment that comprisesor consists essentially of (i) activating a histamine receptor selectedfrom the group consisting of at least one of a histamine H3 receptor anda histamine H4 receptor by administering to a subject a first dose of atherapeutic agent (such as histamine or a histamine salt) in the rangeof 0.01 pg to 10 pg; (ii) activating a histamine receptor selected fromthe group consisting of at least one of a histamine H3 receptor and ahistamine H4 receptor by administering a second dose of the therapeuticagent; (iii) activating a histamine H1 receptor by administering a thirddose of the therapeutic agent; and (iv) activating a histamine H2receptor by administering a fourth dose of the therapeutic agent. Asecond therapy segment having individual doses is further administeredin which the total amount of therapeutic agent is greater than the totalamount given in the first therapy segment. A third therapy segmenthaving individual doses is further administered in which the totalamount of the therapeutic agent is greater than the amount given in thesecond therapy segment. A fourth, fifth, sixth, etc. therapy segmentwith escalating total dose amounts may be optionally administered. Inone embodiment, the invention includes of a kit or regimen thatcomprises or consists essentially of a therapeutic agent (such ashistamine or a histamine salt) provided in total amount (which can beprovided in single one-time disposable vials, syringes, or ampules)ranging from about 200 ng to 600 ng for the first therapy segment, 2times as much in the second therapy segment, and 1.5 times as much (ascompared to the second therapy segment) in the third therapy segment. Asan example, if the total amount of a therapy segment is 1000 ng, fourvials of individual doses of 1 ng, 10 ng, 100 ng, and 889 ng can beprovided. The volumes of the doses are also altered in severalembodiments. The varying volumes are particularly beneficial, in someembodiments, because increased volumes provide for a differentdistribution and/or pharmacokinetic profile. In some embodiments, theratio of total amounts given in each therapy segment is 1:2:3 (for threesegments), 1:2:3:4 (for four segments), 1:2:3:4:5 (for five segments).In some embodiments, the ratio of individual doses within in a giventherapy segment is 1:10³:10⁶:3.5×10⁶.

In some embodiments, the method is used to treat imbalances of histamine(the imbalance being evidenced by sub-optimal or supra-optimal histaminelevels in the bloodstream and/or urine, and/or other symptoms orcharacteristics of histamine imbalance). Thus, in several embodiments,there is provided a method of lowering histamine levels in a subject(e.g., a human patient) having a histamine level above a level requiredfor optimum histamine function (as in histadelia), comprisingadministering histamine thereof to the subject according to the dosingregimens disclosed herein.

As used herein, the terms “treating” and “treatment”, shall be giventheir ordinary meanings and shall also include providing a therapy to apatient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. The terms include activetreatment (e.g., treatment directed specifically toward the improvementof a disease, pathological condition, or disorder) and causal treatment(e.g., treatment directed toward removal of the cause of the associateddisease, pathological condition, or disorder). In addition, these termsshall also include palliative treatment (e.g., treatment designed forthe relief of symptoms), preventative treatment (e.g., treatmentdirected to minimizing or partially or completely inhibiting thedevelopment of an associated disease, pathological condition, ordisorder) and supportive treatment (e.g., treatment employed tosupplement another specific therapy directed toward the improvement ofthe associated disease, pathological condition, or disorder).

In several embodiments, the invention comprises selective activation anddeactivation of the histamine receptors, namely H1, H2, H3 and H4.Histamine or other therapeutic agents that bind or block thesereceptors, or increase or decrease the ability of histamine (endogenousor exogenous histamine) to bind to the receptors are used in severalembodiments. In some embodiments, the invention comprises thedownregulation of the H1 receptor and the upregulation of one, two orall of the H2, H3 and H4 receptor. In several embodiments, the inventionincludes therapeutic agents that regulate the endogenous histaminesystem. These therapeutic agents are provided in dosing schedules asdescribed herein according to several embodiments. Thus, instead of (orin addition to) affecting histamine receptors directly, a therapeuticagent that increases or decreases the manufacture, release,modification, uptake or degradation of histamine is provided. In oneembodiment, selective histamine reuptake inhibitors are used. In someembodiments, therapeutic agents that up-regulate or down-regulatemethyltransferase and/or diamine oxidase are used to decrease orincrease endogenous histamine. Compositions that includemethyltransferase and/or diamine oxidase, or agents with similarfunction, are provided in some embodiments.

In several embodiments, therapeutic agents that regulate endogenous GABAare provided, which in turn affects endogenous release of histamine. Inone embodiment, histamine release is modulated by endogenous GABAthrough GABA-A and/or GABA-B receptors. In one embodiment, therapeuticagents that regulate GABA-B receptors or other receptors located on thehistaminergic nerve terminals that modulate histamine release (e.g.,pre-synaptically or post-synaptically) are provided.

In several embodiments, there is also provided a method of increasinghistamine levels in a subject (e.g., a human patient) having a histaminelevel below a level required for optimum histamine function (as inhistapenia), comprising administering a therapeutically effective amountof a therapeutic agent (e.g., histamine) to a subject according to thedosing regimens disclosed herein. As used herein, the term“therapeutically effective amount” shall be given its ordinary meaningand shall also include an amount of a therapeutic agent sufficient toelicit a desired biological response. Depending on the embodiment, thetherapeutically effective amount may depend on the age, sex and weightof the patient, and/or the current medical condition of the patient.

In several embodiments, there is also provided a method for restoringhistamine balance in a subject by normalizing activity of histaminereceptors through multiple doses administered in successive therapysegments, comprising administering a first therapy segment, that firsttherapy segment comprising activating a histamine H3 receptor byadministering to a subject a first dose of a histamine receptoractivator, activating a histamine H4 receptor by administering to asubject a second dose of the histamine receptor activator, activating ahistamine H1 receptor by administering to a subject a third dose of thehistamine receptor activator, activating a histamine H2 receptor byadministering to a subject a fourth dose of the histamine receptoractivator, and administering a second therapy segment, comprisingadministering the histamine receptor activator in an amount greater thanthe amount administered in the first therapy segment, and administeringa third therapy segment, comprising administering the histamine receptoractivator in an amount greater than the amount administered in thesecond therapy segment. In additional embodiments, there is alsoprovided a method for restoring histamine balance in a subject bynormalizing activity of histamine receptors through multiple dosesadministered in successive therapy segments, comprising administering afirst therapy segment, that first therapy segment comprising activatingone or more of a histamine H3 receptor and a histamine H4 receptor byadministering to a subject a first dose of a histamine receptoractivator, activating a one or more of a histamine H3 receptor and ahistamine H4 receptor by administering to a subject a second dose of thehistamine receptor activator, activating a histamine H1 receptor byadministering to a subject a third dose of the histamine receptoractivator, activating a histamine H2 receptor by administering to asubject a fourth dose of the histamine receptor activator, andadministering a second therapy segment, comprising administering thehistamine receptor activator in an amount greater than the amountadministered in the first therapy segment, and administering a thirdtherapy segment, comprising administering the histamine receptoractivator in an amount greater than the amount administered in thesecond therapy segment. In several embodiments, the increasing amount ofthe histamine receptor activator administered in each successive therapysegment suppresses activity of the histamine H1 receptor and enhancesactivity of a histamine receptor selected from the group consisting ofthe histamine H2, H3, and H4 receptors, thereby normalizing the activityof the histamine receptors and restoring histamine balance.

In several embodiments, there is also provided a method for restoringhistamine balance in a subject by normalizing activity of histaminereceptors through multiple doses administered in successive therapysegments, comprising administering a first therapy segment to thesubject, the first segment comprising administering to a subject a firstdose of a therapeutic agent that binds a histamine H3 receptor byadministering to the subject a first dose of a therapeutic agent,administering to the subject a second dose of a therapeutic agent thatbinds a histamine H4 receptor by administering to the subject a seconddose of the therapeutic agent, administering to the subject a first doseof a therapeutic agent that binds a histamine H1 receptor byadministering to the subject a third dose of the therapeutic agent,administering to the subject a first dose of a therapeutic agent thatbinds a histamine H2 receptor by administering to the subject a fourthdose of the therapeutic agent, administering a second therapy segment tothe subject, the second segment comprising administering the therapeuticagent in an amount greater than the amount administered in the firsttherapy segment, and administering a third therapy segment to thesubject, the third segment comprising administering the therapeuticagent in an amount greater than the amount administered in the secondtherapy segment. Additionally, in several embodiments, there is alsoprovided a method for restoring histamine balance in a subject bynormalizing activity of histamine receptors through multiple dosesadministered in successive therapy segments, comprising administering afirst therapy segment to the subject, the first segment comprisingadministering to a subject a first dose of a therapeutic agent thatbinds a histamine receptor selected from the group consisting of ahistamine H3 receptor and a histamine H4 receptor by administering tothe subject a first dose of a therapeutic agent, administering to thesubject a second dose of a therapeutic agent that binds a histaminereceptor selected from the group consisting of a histamine H3 receptorand a histamine H4 receptor by administering to the subject a seconddose of the therapeutic agent, administering to the subject a first doseof a therapeutic agent that binds a histamine H1 receptor byadministering to the subject a third dose of the therapeutic agent,administering to the subject a first dose of a therapeutic agent thatbinds a histamine H2 receptor by administering to the subject a fourthdose of the therapeutic agent, administering a second therapy segment tothe subject, the second segment comprising administering the therapeuticagent in an amount greater than the amount administered in the firsttherapy segment, and administering a third therapy segment to thesubject, the third segment comprising administering the therapeuticagent in an amount greater than the amount administered in the secondtherapy segment.

There is also provided, in several embodiments, methods fordown-regulating a histamine H1 receptor comprising administering a firsttherapy segment, comprising administering to a subject a first dose of atherapeutic agent that binds a histamine H3 receptor administering tothe subject a first dose of the therapeutic agent, administering to thesubject a second dose of a therapeutic agent that binds a histamine H4receptor by administering to the subject a second dose of thetherapeutic agent, administering to the subject a first dose of atherapeutic agent that binds a histamine H1 receptor by administering tothe subject a third dose of the therapeutic agent, administering to thesubject a first dose of a therapeutic agent that binds a histamine H2receptor by administering to the subject a fourth dose of thetherapeutic agent, administering to the subject a second therapysegment, the second segment comprising administering the therapeuticagent in an amount greater than the amount administered in the firsttherapy segment, administering a third therapy segment to the subject,the third segment comprising: administering the therapeutic agent in anamount greater than the amount administered in the second therapysegment, wherein the increasing amount of the therapeutic agentadministered in each successive therapy segment down-regulates activityof the histamine H1 receptor There is also provided, in severalembodiments, methods for down-regulating a histamine H1 receptorcomprising administering a first therapy segment, comprisingadministering to a subject a first dose of a therapeutic agent thatbinds a histamine receptor selected from the group consisting of ahistamine H3 receptor and a histamine H4 receptor by administering tothe subject a first dose of the therapeutic agent, administering to thesubject a second dose of a therapeutic agent that binds a histaminereceptor selected from the group consisting of a histamine H3 receptorand a histamine H4 receptor by administering to the subject a seconddose of the therapeutic agent, administering to the subject a first doseof a therapeutic agent that binds a histamine H1 receptor byadministering to the subject a third dose of the therapeutic agent,administering to the subject a first dose of a therapeutic agent thatbinds a histamine H2 receptor by administering to the subject a fourthdose of the therapeutic agent, administering to the subject a secondtherapy segment, the second segment comprising administering thetherapeutic agent in an amount greater than the amount administered inthe first therapy segment, administering a third therapy segment to thesubject, the third segment comprising: administering the therapeuticagent in an amount greater than the amount administered in the secondtherapy segment, wherein the increasing amount of the therapeutic agentadministered in each successive therapy segment down-regulates activityof the histamine H1 receptor. Optionally, additional therapy segmentscan be administered as well.

In several embodiments, the histamine receptor activator is administeredin one or more of varied concentration (e.g., increased concentration ascompared to a preceding administration), varied volume (e.g., increasedconcentration as compared to a preceding administration), or with avaried timing (e.g., the frequency of administration is reduced withsuccessive segments). The tri-variable approach is beneficial in severalembodiments, because cellular distribution and receptor contact can beadjusted. In this manner, selective activation of receptors can beachieved. Moreover, in several embodiments, the sequence of receptoractivation can be altered depending on the condition being treated. Forexample, in several embodiments, a therapeutic agent can be administeredat a dose sufficient to preferentially activate or bind an H1 receptor,and increase histamine levels in a subject (e.g., to treat histapenia).Alternatively, a therapeutic agent can be administered at a dosesufficient to preferentially activate or bind H2 and/or H3 receptor(which in several embodiments suppresses the activity and/or expressionof the histamine H1 receptor and leads to reduction in histamine levels,such as when treating histadelia).

In several embodiments, the therapeutic agent and/or histamine receptoractivator comprises histamine. In several embodiments, the histaminereceptor activator comprises a histamine salt selected from the groupconsisting of histamine diphosphate, histamine phosphate, and histaminedihydrochloride. Combinations of these salts or other various salts ofhistamine may also be used, depending on the embodiment.

In several embodiments the successive therapy segments (e.g., thesecond, third, etc. therapy segment) comprises at least a first dose, asecond dose, a third dose and a fourth dose of the histamine receptoractivator. Optionally several embodiments comprise administering atleast a fourth therapy segment, wherein the fourth therapy segmentcomprises administering the histamine receptor activator in an amountgreater than the amount administered in the third therapy segment.

In several embodiments, the total dose of the histamine receptoractivator in the first therapy segment ranges from about 100 ng to 700ng, including about 200 ng to about 600 ng, about 300 ng to about 500ng, about 400 ng, and overlapping ranges thereof. In severalembodiments, the total dose of the histamine receptor activator in thesecond therapy segment ranges from about 600 ng to about 1000 ng,including about 600 ng to about 800 ng, about 650 ng to about 1000 ng,about 800 ng to about 1000 ng, and overlapping ranges therein. Inseveral embodiments, the total dose of the histamine receptor activatorin the third therapy segment ranges from about 1050 ng to about 1600 ng,including about 1050 ng to about 1200 ng, about 1200 ng to about 1300ng, about 1300 ng to about 1400 ng, about 1400 ng to about 1500 ng,about 1500 ng to about 1600 ng, about 1050 ng to about 1500 ng andoverlapping ranges thereof. In several embodiments, these doses areprovided in varying volumes using a multi-variable approach, which insome embodiments, results in certain histamine receptors being activatedto a greater degree than other histamine receptors. For example, theaffinities in Table 1 are exploited in several embodiments of theinvention to induce a targeted, sequenced and controlled histaminereceptor activation pattern.

In several embodiments, the second therapy segment is longer in timethan the first therapy segment and wherein the third therapy segment islonger in time than the second therapy segment. In embodiments whereinadditional therapy segments are administered, successive therapysegments are optionally longer in duration than those preceding it(e.g., each successive segment is longer in duration). In severalembodiments, the frequency of administration of the therapeutic agent(e.g., a histamine receptor activator) remains constant from segment tosegment, such that the increased duration of successive segments reducesthe administration frequency (as compared to the previous segment). Byway of example, in several embodiments, the first therapy segment occursover 10-16 days, the second therapy segment occurs over 20-35 days, andthe third therapy segment occurs over 38-50 days. In additionalembodiments, the first therapy segment is optionally administered on acompressed time-frame. For example, in several embodiments the dosescomprising the first therapy segment are, in several embodiments,administered within a shortened time frame (e.g., about 30 seconds toabout 5 minutes). As a result, the modulation of the various receptorsoccurs on a reduced time-frame, and in some embodiments, simultaneously.In such embodiments, the first therapy segment advantageously“jump-starts” the regimen by concurrent receptor modulation. In severalembodiments, the first therapy segment comprises simultaneously deliveryof each of the doses within the segment. In several embodiments, thefirst therapy segment is compressed to occur over about 1-2 minutes,about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-10minutes, about 10-20 minutes, about 20-30 minutes, and overlappingranges thereof.

In several embodiments, the administration of the therapeutic agent(e.g., a histamine receptor activator) comprises subcutaneous injectionof histamine or a histamine salt, wherein the total dose of the firsttherapy segment is about 200 ng to about 600 ng, wherein the total doseof the second therapy segment is about 650 ng to about 1000 ng, whereinthe total dose of the third therapy segment is about 1050 ng to about1500 ng, wherein the second therapy segment is longer than the firsttherapy system, and wherein the third therapy segment is longer than thesecond therapy system.

In additional embodiments, administration of the therapeutic agent(e.g., a histamine receptor activator) comprises intravenous injection.In still further embodiments, the therapeutic agent (e.g., a histaminereceptor activator) is administered by an oral delivery route. In stillfurther embodiments, the therapeutic agent (e.g., a histamine receptoractivator) is administered by inhalation. In still further embodiments,the therapeutic agent (e.g., a histamine receptor activator) isadministered through a transdermal patch. In several embodiments, theadministration of the therapeutic agent (e.g., a histamine receptoractivator) comprises a route selected from the group consisting ofsubcutaneous, intraarterial, intravenous, and combinations thereof.Depending on the embodiment, a given segment may be delivered by a firstroute of administration (e.g., subcutaneous), while another segment isdelivered by a different route (e.g., oral). In several embodiments,modification of the administration route reduces risk of side effectsassociated with a single administration route. Moreover, in severalembodiments, the change in administration route enables a greaterproportion of the histamine receptors in certain organ banks to bereached. For example, oral administration may facilitate restoration ofbalance of histamine receptor activity in the gastrointestinal tract toa greater degree than intravenous administration. In severalembodiments, the therapeutic agent is delivered by a non-invasiveadministration route. In several embodiments, the therapeutic agent isself-administered. In several embodiments, the therapeutic agent isadministered by, for example, a nurse, a physician, a hospice careworker, and/or another medical provider, while in some embodiments, thetherapeutic agent is administered by a an individual who is not amedical professional (e.g., a non-medical professional, such as, forexample, an acquaintance, family member, spouse, etc.).

In several embodiments, the subject receiving therapy is susceptible tomigraine headaches and the restored histamine balance leads to areduction in duration, frequency and/or intensity of migraine headaches.

In several embodiments, the subject receiving therapy has histadelia andthe restored histamine balance treats the histadelia. In severalembodiments, the subject receiving therapy has histapenia and therestored histamine balance treats the histapenia.

In several embodiments, therapeutic agent (e.g., a histamine receptoractivator) is provided as a liquid formulation. In several embodiments,the first dose of the histamine receptor activator in the first therapysegment has a concentration ranging from between about 0.1 pg/mL toabout 10 pg/mL, including about 0.5 pg/mL, about 1 pg/mL, about 2 pg/mL,about 3 pg/mL, about 4 pg/mL, about 5 pg/mL, about 6 pg/mL, about 7pg/mL, about 8 pg/mL, about 9 pg/mL, about 10 pg/mL, and concentrationstherebetween.

In several embodiments, the second dose of the histamine receptoractivator in the first therapy segment has a concentration ranging frombetween about 0.1 ng/mL to about 10 ng/mL, including about 0.5 ng/mL,about 1.0 ng/mL, about 2 ng/mL, about 3 ng/mL, about 4 ng/mL, about 5ng/mL, about 6 ng/mL, about 7 ng/mL, about 8 ng/mL, about 9 ng/mL, about10 ng/mL, and concentrations therebetween.

In several embodiments, the third dose of the histamine receptoractivator in the first therapy segment has a concentration ranging frombetween about 0.1 μg/mL to about 2.999 μg/mL (e.g., about 0.1 μg/mL toabout 2.999 μg/mL), including about 0.1 μg/mL, about 0.5 μg/mL, about 1μg/mL, about 1.5 μg/mL, about 2 μg/mL, about 2.5 μg/mL, about 2.999μg/mL, and concentrations therebetween. In several embodiments, thethird dose of the histamine receptor activator in the first therapysegment has a concentration ranging from between about 0.1 μg/mL toabout 3.49 μg/mL, including about 0.1 μg/mL, about 0.5 μg/mL, about 1μg/mL, about 1.5 μg/mL, about 2 μg/mL, about 2.5 μg/mL, about 3 μg/mL,about 3.49 μg/mL, and concentrations therebetween.

In several embodiments, the fourth dose of the histamine receptoractivator in the first therapy segment has a concentration ranging frombetween about 3.0 μg/mL to about 10 μg/mL, including about 3 μg/mL,about 3.5 μg/mL, about 4 μg/mL, about 4.5 μg/mL, about 5 μg/mL, about 6μg/mL, about 7 μg/mL, about 8 μg/mL, about 9 μg/mL, about 10 μg/mL, andconcentrations therebetween. In several embodiments, the fourth dose ofthe histamine receptor activator in the first therapy segment has aconcentration ranging from between about 0.35 μg/mL to about 10 μg/mL,including about 0.35 μg/mL, about 0.75 μg/mL, about 1 μg/mL, about 1.5μg/mL, about 2 μg/mL, about 2.5 μg/mL, about 3 μg/mL, about 3.5 μg/mL,about 4 μg/mL, about 4.5 μg/mL, about 5 μg/mL, about 6 μg/mL, about 7μg/mL, about 8 μg/mL, about 9 μg/mL, about 10 μg/mL, and concentrationstherebetween.

In several embodiments, the volume of each dose in the first therapysegment ranges from between about 0.01 mL to about 1.0 mL, includingabout 0.1 mL, about 0.5 mL, about 0.75 mL, about 1 mL, and volumestherebetween. In several embodiments, the histamine receptor activatoris administered with a frequency of between one and three times per weekduring the first therapy segment, such as, for example, two times perweek during the first therapy segment.

In several embodiments, the second therapy segment comprises a firstdose, a second dose, a third dose, and a fourth dose, and the first dosein the second therapy segment has a concentration ranging from betweenabout 0.1 pg/mL to about 10 pg/mL (e.g., about 0.1 pg/mL, about 1 pg/mL,about 5 pg/mL, about 10 pg/mL and concentrations therebetween). Inseveral embodiments, the second dose in the second therapy segment has aconcentration ranging from between about 0.1 ng/mL to about 10 ng/mL(e.g., about 0.5 ng/mL, about 1.0 ng/mL, about 5 ng/mL, about 10 ng/mL,and concentrations therebetween). In several embodiments, the third dosein the second therapy segment has a concentration ranging from betweenabout 0.1 μg/mL to about 2.999 μg/mL (e.g., about 0.1 μg/mL, about about1 μg/mL, about 2 μg/mL, about 2.5 μg/mL, about 2.999 μg/mL, andconcentrations therebetween). In several embodiments, the fourth dose inthe second therapy segment has a concentration ranging from betweenabout 3.0 μg/mL to about 10 μg/mL (e.g., about 3.0 μg/mL, about 3.5μg/mL, about 4 μg/mL, about 4.5 μg/mL, about 6 μg/mL, about 8 μg/mL,about 10 μg/mL, and concentrations therebetween). In additionalembodiments, the third dose in the second therapy segment has aconcentration ranging from between about 0.1 μg/mL to about 3.49 μg/mL(e.g., about 0.1 μg/mL, about about 1 μg/mL, about 2 μg/mL, about 3μg/mL, about 3.49 μg/mL, and concentrations therebetween). In severalembodiments, the fourth dose in the second therapy segment has aconcentration ranging from between about 0.35 μg/mL to about 10 μg/mL(e.g., about 0.35 μg/mL, about 1 μg/mL, about 1.5 μg/mL, about 3 μg/mL,about 3.5 μg/mL, about 4 μg/mL, about 4.5 μg/mL, about 6 μg/mL; about 8μg/mL, about 10 μg/mL, and concentrations therebetween).

In several embodiments, the volume of each dose in the second therapysegment ranges from between about 0.02 mL to about 2.0 mL, such as, forexample, about 0.2 mL, about 0.5 mL, about 0.75 mL, about 1 mL, about1.5 mL, about 2 mL and volumes therebetween.

In several embodiments, the second segment comprises administration ofthe histamine receptor activator with a frequency of between 2 times perweek and once every 10 days during the second therapy segment, such as,for example, once per week, twice, per week, once every eight days, onceevery ten days, and frequencies therebetween.

In several embodiments, the third therapy segment comprises a firstdose, a second dose, a third dose, and a fourth dose, and the first dosein the third therapy segment has a concentration ranging from betweenabout 0.1 pg/mL to about 10 pg/mL (e.g., about 0.1 pg/mL, about 1 pg/mL,about 5 pg/mL, about 10 pg/mL and concentrations therebetween). Inseveral embodiments, the second dose in the third therapy segment has aconcentration ranging from between about 0.1 ng/mL to about 10 ng/mL(e.g., about 0.5 ng/mL, about 1.0 ng/mL, about 5 ng/mL, about 10 ng/mL,and concentrations therebetween). In several embodiments, the third dosein the third therapy segment has a concentration ranging from betweenabout 0.1 μg/mL to about 2.999 μg/mL (e.g., about 0.1 μg/mL, about about1 μg/mL, about 2 μg/mL, about 2.999 μg/mL, and concentrationstherebetween). In several embodiments, the fourth dose in the thirdtherapy segment has a concentration ranging from between about 3.0 μg/mLto about 10 μg/mL (e.g., about 3 μg/mL, about 3.5 μg/mL, about 4 μg/mL,about 4.5 μg/mL, about 6 μg/mL, about 8 μg/mL, about 10 μg/mL, andconcentrations therebetween). In several embodiments, the third dose inthe third therapy segment has a concentration ranging from between about0.1 μg/mL to about 3.49 μg/mL (e.g., about 0.1 μg/mL, about about 1μg/mL, about 2 μg/mL, about 3 μg/mL, about 3.49 μg/mL, andconcentrations therebetween). In several embodiments, the fourth dose inthe third therapy segment has a concentration ranging from between about0.35 μg/mL to about 10 μg/mL (e.g., about 0.35 μg/mL, about 1 μg/mL,about 1.5 μg/mL, about 3 μg/mL, about 3.5 μg/mL, about 4 μg/mL, about4.5 μg/mL, about 6 μg/mL, about 8 μg/mL, about 10 μg/mL, andconcentrations therebetween).

In several embodiments, the volume of each dose in the third therapysegment ranges from between about 0.03 mL to about 3.0 mL, such as, forexample, about 0.3 mL, about 0.5 mL, about 0.75 mL, about 1 mL, about2.0 mL, about 3.0 mL and volumes therebetween.

In several embodiments, the third segment comprises administration ofthe histamine receptor activator with a frequency of between once perweek and once every two weeks during the third therapy segment, such as,for example, once per week, once every eight days, once every ten days,once every twelve days, once every fourteen days, and frequenciestherebetween.

Additionally, there are provided, in several embodiments, methods forreducing, ameliorating, preventing, and/or inhibiting the frequency,duration and/or intensity of migraine headaches in a subject throughnormalization of the activity and/or expression of one or more histaminereceptors, comprising identifying a subject susceptible to migraineheadaches and having a histamine imbalance, administering to the subjecta first histamine dosing segment comprising a first, a second, a third,and a fourth dose of histamine, wherein the first dose is administeredsubcutaneously at a concentration between about 0.1 pg/mL to about 10pg/mL and activates a histamine receptor selected from the groupconsisting of a histamine H3 receptor and a histamine H4 receptor,wherein the second dose of histamine is administered subcutaneously at aconcentration between about 0.1 ng/mL to about 10 ng/mL and activates ahistamine receptor selected from the group consisting of a histamine H3receptor and a histamine H4 receptor, wherein the third dose ofhistamine is administered subcutaneously at a concentration betweenabout 0.1 μg/mL to about 3.49 μg/mL (for example, between about 0.1μg/mL to about 2.999 μg/mL) and activates a histamine H1 receptor,wherein the fourth dose of histamine is administered subcutaneously at aconcentration between about 0.35 μg/mL to about 10 μg/mL (for example,about 3.0 μg/mL to about 10 μg/mL) and activates a histamine H2receptor, wherein each dose in the first dosing segment has the samevolume and wherein the volume ranges from between about 0.01 mL to about1.0 mL, wherein each successive dose comprises a larger amount ofhistamine as compared to the preceding dose; administering to thesubject a second histamine dosing segment comprising a first, a second,a third, and a fourth dose of histamine, wherein the concentration ofthe histamine administered in each dose is equivalent to thecorresponding concentration of histamine each dose of the first dosingsegment, wherein each dose in the second dosing segment has the samevolume, and wherein the volume ranges from between about 0.02 mL toabout 2.0 mL, wherein the total amount of histamine delivered in thesecond dosing segment is greater than the amount delivered in the firstdosing segment; and administering to the subject a third histaminedosing segment comprising a first, a second, a third, and a fourth doseof histamine, wherein the concentration of the histamine administered ineach dose is equivalent to the corresponding concentration of histamineeach dose of the first dosing segment, wherein each dose in the thirddosing segment has the same volume, and wherein the volume ranges frombetween about 0.03 mL to about 3.0 mL, wherein the total amount ofhistamine delivered in the third dosing segment is greater than theamount delivered in the second dosing segment. In several embodiments,the increase in the amount of histamine administered with eachsuccessive dosing segment suppresses activity of the H1 receptor andenhances activity of the H2, H3 and/or H4 receptors, thereby normalizingthe activity and/or expression of the histamine receptors and reducingthe duration, frequency and/or intensity of migraine headaches in thesubject.

In several embodiments, the ratio of individual doses within any of thefirst, second, or third therapy segment is 1:10³:10⁶:3.5×10⁶. Asdiscussed above, these ratios (either by adjustment of volume orconcentration) can be adjusted if a subject requires an increase or adecrease in histamine activity (or receptor expression). The methodsalso optionally include administration of an additional agonist or anantagonist of any of the histamine H1, H2, H3, or H4 receptors.Moreover, the methods, in several embodiments, include one or more ofidentifying a subject having histamine imbalance (such as for example,but measuring the serum and/or urine histamine concentrations) andinstructing administration of the therapeutic agent.

There are also provided herein histamine receptor activators for use inup-regulating certain histamine receptors and down-regulating otherhistamine receptors to balance the histamine system, which in turn maybe useful for the treatment of migraine headaches, Parkinson's Disease,Alzheimer's Disease, coronary disease, leukemia, amyotrophic lateralsclerosis, epilepsy histadelia and/or histapenia and other disorders. Inseveral embodiments, there is additionally provided a histamine receptoractivator(s) for use in the treatment of migraine headaches, Parkinson'sDisease, Alzheimer's Disease, coronary disease, leukemia, amyotrophiclateral sclerosis and/or epilepsy, histadelia and/or histapenia byadministration of a dosage of the activator divided into at least threetherapy segments, wherein the total dose of the histamine receptoractivator in the first therapy segment is about 200 ng to about 600 ng,wherein the total dose of the histamine receptor activator in the secondtherapy segment is about 650 ng to about 1000 ng, and wherein the totaldose of the histamine receptor activator in the third therapy segment isabout 1050 ng to about 1500 ng.

There is also provided a histamine receptor activator for use in thetreatment of migraine headaches by subcutaneous administration of saidhistamine receptor activator. In several embodiments, the histaminereceptor activator comprises histamine, and/or a histamine salt selectedfrom the group consisting of one or more of histamine diphosphate,histamine phosphate, and histamine dihydrochloride.

Also provided herein is a histamine receptor activator (or activators)for use in the treatment of migraine headaches, Parkinson's Disease,Alzheimer's Disease, coronary disease, leukemia, amyotrophic lateralsclerosis epilepsy, histadelia and/or histapenia (or other ailments) inpatients showing an elevated amount of circulating histamine as well asailments in which patients show a reduced amount of circulatinghistamine. Thus, in several embodiments, the invention comprises ahistamine receptor activator for regulating endogenous histamine levels,including but not limited to use in the treatment of migraine headaches,Parkinson's Disease, Alzheimer's Disease, coronary disease, leukemia,amyotrophic lateral sclerosis, epilepsy, histadelia and/or histapenia torestore histamine balance in the subject.

In several embodiments, the invention comprises a histamine receptoractivator (or activators) for use in the treatment of migraineheadaches, Parkinson's Disease, Alzheimer's Disease, coronary disease,leukemia, amyotrophic lateral sclerosis, epilepsy, histadelia and/orhistapenia by inhibiting the activity and/or expression of a histaminereceptor selected from the group consisting of the histamine H1receptor, the histamine H2 receptor, the histamine H3 receptor, and thehistamine H4 receptor. In several embodiments, the histamine receptoractivator inhibits the activity and/or expression of the histamine H1receptor.

In several embodiments, the invention comprises a histamine receptoractivator for use in the treatment of diseases associated with theover-expression and/or over-activity of the histamine H1 receptor, suchas, for example, one or more of migraine headaches, Parkinson's Disease,Alzheimer's Disease, coronary disease, leukemia, amyotrophic lateralsclerosis epilepsy, histadelia and/or histapenia. Similarly, there isprovided, in several embodiments, a histamine receptor activator for usein the treatment of diseases associated with the under-expression and/orunder-activity one or more of the histamine H2, H3, and/or H4 receptors,such as, for example, migraine headaches, Parkinson's Disease,Alzheimer's Disease, coronary disease, leukemia, amyotrophic lateralsclerosis, epilepsy, histadelia and/or histapenia.

In several embodiments, the invention comprises, a histamine receptoractivator(s) for use in the treatment of migraine headaches, Parkinson'sDisease, Alzheimer's Disease, coronary disease, leukemia, amyotrophiclateral sclerosis, epilepsy, histadelia and/or histapenia by combined,sequential, or separate administration with a complete or partialantagonist of a histamine H1 receptor.

In several embodiments, the invention comprises an inhibitor of theactivity and/or expression of a histamine H1 receptor for use in thetreatment of migraine headaches, Parkinson's Disease, Alzheimer'sDisease, coronary disease, leukemia, amyotrophic lateral sclerosis,epilepsy, histadelia and/or histapenia.

Additionally provided herein is an escalating histamine dosing regimencomprising a first dosing segment comprising two or more sequentialdoses of histamine separated by a first time interval, wherein the dosesincrease in histamine concentration from dose to dose while theadministered volume of each dose stays constant and a second dosingsegment comprising two or more sequential doses of histamine separatedby a second time interval, wherein the doses increase in histamineconcentration from dose to dose while the administered volume of eachdose stays constant wherein the volume of each histamine dose in thesecond dosing segment is greater than the volume of each histamine dosein the first dosing segment, and the second time interval is longer thanthe first time interval. In several embodiments, the first dosingsegment comprises a first, a second, a third, and a fourth dose. In somesuch embodiments, the first dose is administered subcutaneously at aconcentration of 1.1 ng/mL +/−20-30% and activates a histamine H3receptor, the second dose of histamine is administered subcutaneously ata concentration of 3 ng/mL +/−40-50% and activates a histamine H4receptor, the third dose of histamine is administered subcutaneously ata concentration of 1.1 μg/mL +/−20-30% and activates a histamine H1receptor, and the fourth dose of histamine is administeredsubcutaneously at a concentration of 3.33 μg/mL +/−20-30% and activatesa histamine H2 receptor.

In several embodiments of the histamine dosing regimen, theconcentrations of histamine administered during the first dosing segmentare the same as the concentrations of histamine administered during thesecond dosing segment, the number of doses administered during the firstdosing segment is equal to the number of doses administered during thesecond dosing segment, the first dosing segment and the second dosingsegment are separated by the first time interval.

Optionally, the histamine dosing regimen may further comprise a thirddosing segment comprising two or more sequential doses of histamineseparated by a third time interval, wherein the doses increase inhistamine concentration from dose to dose while the administered volumeof each dose stays constant, the volume of each dose in the third dosingsegment is greater than the volume of each dose administered in thesecond dosing segment, and the third time interval is longer than thesecond time interval. In such, embodiments, the concentrations ofhistamine administered during the third dosing segment are the same asthe concentrations of histamine administered during the second dosingsegment, the number of doses administered during the third dosingsegment is equal to the number of doses administered during the seconddosing segment, and the second dosing segment and the third dosingsegment are separated by the second time interval.

Depending on the embodiment, each dosing segment may comprise three ormore doses, for example, in some embodiments, each dosing segmentcomprises four doses, five doses, six doses, eight doses, or ten doses.

As discussed herein, there are also provided, in several embodiments,extended duration regimens, such as those comprising up to ten (or more)sequential dosing segments, wherein each dosing segment comprises two ormore sequential doses of histamine separated by one or more equal timeintervals, the doses in each segment increase in histamine concentrationfrom dose to dose while the administered volume of each dose staysconstant, the volume of each histamine dose in a succeeding dosingsegment is greater than the volume of each histamine dose in thepreceding dosing segment, the time interval in each succeeding dosingsegment is longer than the time interval in the preceding dosingsegment, the concentrations of histamine administered are the same ineach dosing segment, the number of doses administered during eachsegment is equal, and/or each succeeding dosing segment is separate fromthe immediately preceding dosing segment by the time interval observedfor the immediately preceding dosing segment.

For example, in some extended dosing regimen embodiments comprising tendosing segments, the volume per dose in the first segment is about 0.1mL and the volume of each dose in each succeeding segment is about 0.1mL greater than the volume administered in the immediately precedingsegment.

In several embodiments, the histamine concentration of each dose in eachsegment ranges from about 1 attogram/ml to 20 μg/ml, such as for exampleconcentrations ranging (for each dose) from about 1 pg/ml to about 3.5μg/ml. (or, as in one embodiment, 1 pg/ml to about 2.999 μg/ml). Inseveral embodiments, the first dosing interval ranges from about one dayto one week in duration, and the second dosing interval ranges fromabout three days to two weeks in duration. Subsequent dosing intervals,in several embodiments, successively increase in duration, such as forexample, a third dosing interval may range from about one week to aboutthree weeks.

Depending on the embodiment, histamine used in the histamine dosingregimen can be present as a free base, a pharmaceutically acceptablesalt thereof, or combinations thereof. Depending on the embodiments, theroute of administration is via subcutaneous, intravenous,intra-muscular, infusion, transdermal, inhalation and/or sub-lingualadministration.

There are also provided herein methods for lowering histamine levels ina human patient having a histamine level above a level required foroptimum histamine function, comprising administering histamine or apharmaceutically acceptable salt thereof to the patient according to thedosing regimens described herein. A method of increasing histaminelevels in a human patient having a histamine level below a levelrequired for optimum histamine function, comprising administeredhistamine or a pharmaceutically acceptable salt thereof to the patientaccording to the dosing regimens described herein. In severalembodiments, the assessment of the level of histamine required foroptimum histamine function is based on plasma histamine levels or urinehistamine levels, and diagnostic tests for measuring same. In severalembodiments, the level required for optimum histamine function isbetween about 45 and about 50 ng/ml of plasma. However, in severalembodiments, restoration of histamine levels to a level above or belowthat range, but to a concentration that is normal for a particularindividual, is achieved.

In several embodiments, a method for restoring histamine balance isprovided. In some embodiments, normalizing activity of histaminereceptors is achieved through administration of (or instructing theadministration of) multiple doses of a histamine receptor activatoradministered in successive therapy segments. In several embodiments, themethods comprise administering at least a first, a second, and a thirdinitial therapy segments, each of the initial segments comprisingactivating a histamine H3 or H4 receptor by administering to a subject afirst dose of a histamine receptor activator, activating a histamine H1receptor by administering to a subject a second dose of the histaminereceptor activator, activating a histamine H2 receptor by administeringto a subject a third dose of the histamine receptor activator, andadministering a plurality of escalating therapy segments, each of theescalating therapy segments comprising activating a histamine H3 or H4receptor by administering to a subject a first dose of the histaminereceptor activator, activating a histamine H1 receptor by administeringto a subject a second dose of the histamine receptor activator,activating a histamine H2 receptor by administering to a subject a thirddose of the histamine receptor activator thereby normalizing theactivity of the histamine receptors and restoring histamine balance.

In several additional embodiments, a method for restoring histaminebalance is provided, the method comprising normalizing activity ofhistamine receptors through multiple doses administered in successivetherapy segments. In several embodiments normalization of receptoractivity is accomplished by administering, or instructing theadministration of, at least a first, a second, and a third initialtherapy segments, each of the initial segments comprising activation ofa histamine H3 receptor by administering to a subject a first dose of ahistamine receptor activator, activation of a histamine H4 receptor byadministering to a subject a second dose of a histamine receptoractivator, activation of a histamine H1 receptor by administering to asubject a third dose of the histamine receptor activator, activation ofa histamine H2 receptor by administering to a subject a fourth dose ofthe histamine receptor activator, administering, or instructing theadministration of, a plurality of escalating therapy segments, each ofthe escalating therapy segments comprising activation of a histamine H3receptor by administering to a subject a first dose of the histaminereceptor activator, activation of a histamine H4 receptor byadministering to a subject a second dose of the histamine receptoractivator, activation of a histamine H1 receptor by administering to asubject a third dose of the histamine receptor activator, activation ofa histamine H2 receptor by administering to a subject a fourth dose ofthe histamine receptor activator. In several embodiments, the amount ofthe histamine receptor activator in the second initial therapy segmentis greater than the amount of the histamine receptor activator in thefirst initial therapy segment, the amount of the histamine receptoractivator in the third initial therapy segment is greater than theamount of the histamine receptor activator in the second initial therapysegment, the amount of the histamine receptor activator administered ineach successive escalating therapy segment is greater than the precedingescalating therapy segment, and the increasing of amount histaminereceptor activator administered enhances activity of a histaminereceptor selected from the group consisting of the histamine H1, H2, H3,and H4 receptors, thereby normalizing the activity of the histaminereceptors and restoring histamine balance.

In several embodiments, the amount of the histamine receptor activatorin the second initial therapy segment is greater than the amount of thehistamine receptor activator in the first initial therapy segment andthe amount of the histamine receptor activator in the third initialtherapy segment is greater than the amount of the histamine receptoractivator in the second initial therapy segment. In those embodimentswhere additional initial therapy segments are administered, the amountof the histamine receptor activator administered in each successiveinitial therapy segment is greater than the preceding segment. Inseveral embodiments, the amount of the histamine receptor activatoradministered in each successive escalating therapy segment is greaterthan the preceding escalating therapy segment. In several embodiments,the wherein the increasing of amount histamine receptor activatoradministered leads to suppression of the activity of the histamine H1receptor, but enhances activity of a histamine receptor selected fromthe group consisting of the histamine H2, H3, and H4 receptors, therebynormalizing the activity of the histamine receptors and restoringhistamine balance.

There is provided a method for restoring histamine balance in a subjectby normalizing activity of histamine receptors through an escalatingdosing regimen, comprising administering a plurality of therapysegments, each of the segments comprising activating a histamine H3receptor or H4 receptor by administering to a subject a first dose of ahistamine receptor activator, activating a histamine H1 receptor byadministering to a subject a second dose of the histamine receptoractivator, activating a histamine H2 receptor by administering to asubject a third dose of the histamine receptor activator, wherein theamount of the histamine receptor activator administered in eachsuccessive escalating therapy segment is greater than the precedingescalating therapy segment, and wherein the increasing of amounthistamine receptor activator administered leads to suppression of theactivity of the histamine H1 receptor while the activity of a histaminereceptor selected from the group consisting of the histamine H2, H3, andH4 receptors is enhanced, resulting in a normalization of the activityof the histamine receptors and restoring histamine balance.

In several embodiments, the first dose, the second dose, and the thirddose in each escalating therapy segment is administered within a totaltime frame of less than about 5 minutes, (e.g., less than 4 minutes,less than 3 minutes, less than 2 minutes, less than 1 minute).

In several embodiments, the histamine receptor activator compriseshistamine. In additional embodiments, the histamine receptor activatorcomprises a histamine salt selected from the group consisting ofhistamine diphosphate, histamine phosphate, and histaminedihydrochloride.

In several embodiments, the administration of the histamine receptoractivator comprises subcutaneous injection.

Also provided herein is a kit comprising formulations suitable forachieving the histamine normalization methods disclosed herein. Inseveral embodiments, the invention comprises a kit (or dosing regimen)comprising formulations in concentrations set forth on any one of Tables2-7.

In several embodiments, there is a provided a method of restoringhistamine balance, comprising providing at least one histamine receptoractivator and instructing the administration of the composition atconcentrations suitable for activating one or more of the histamine H1,H2, H3, and/or H4 receptors. In several embodiments, the method furthercomprises providing an additional therapeutic composition that caneither agonize or antagonize on or more of the histamine H1, H2, H3,and/or H4 receptors. In several embodiments, the at least one histaminereceptor activator is histamine or a histamine salt. In severalembodiments the at least one histamine receptor activator is provided asa concentrated composition (e.g., a liquid or a solid, such as alyophilized powder) and is suitable for dilution into variousconcentrations that are used to specifically target one or more of thehistamine receptors.

The methods summarized above and set forth in further detail belowdescribe certain actions taken by a practitioner; however, it should beunderstood that they can also include the instruction of those actionsby another party. Thus, actions such as “administering a histamineagonist” include “instructing the administration of a histamineagonist.”

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the chemical structure of histamine.

FIG. 2 depicts a schematic of various signaling pathways in whichhistamine plays a role and examples of symptoms that can result from theactivity of histamine receptors in certain tissues.

FIG. 3 depicts general schematic of histamine signaling through aG-protein coupled receptor.

FIG. 4 depicts a summary of previous clinical data related to serumhistamine concentrations in various populations during symptom freestates.

FIG. 5 depicts a summary of previous clinical data related to serumhistamine concentrations in various populations during migraine events.

FIG. 6 depicts a summary of previous clinical data related to brainhistamine levels in patients with Parkinson's disease versus healthysubjects

FIG. 7 depicts a summary of previous clinical data related to brainhistamine concentration in patients with Alzheimer's disease versushealthy subjects

FIG. 8 depicts a summary of previous clinical data related to histamineblood concentration in patients with coronary disease versus healthysubjects

FIG. 9 depicts a summary of previous clinical data related to plasmahistamine levels in patients with Myelogenous Leukemia versus healthysubjects

DETAILED DESCRIPTION

Several embodiments of the invention employ a multi-variable approach totreat imbalances of the histamine system. The multi-variable approach,which includes altering concentration, volume, and timing in someembodiments, may advantageously affect in vivo distribution to achieveselective (or enhanced) activation of certain histamine receptors. Byemploying a targeted and controlled pattern of receptor activation,receptors can be up and/or down regulated to rebalance the histaminesystem and offer profound relief for those who suffer from dysregulationof the histamine system.

General

Histamine, first identified as an autacoid having vasoactive properties,and also referred to in some contexts as “substance H”, is a member ofthe biogenic amines family and is synthesized from the amino acidhistidine by the activity of L-histidine decarboxylase (HDC). Histadinedecarboxylase (HDC) is an enzyme that is expressed in various cellsthroughout the body, including central nervous systems (neurons),gastric-mucosa (parietal cells), mast cells (which can contain ˜3 pg ofhistamine per cell), and basophils (which can contain ˜1 pg of histamineper cell). Histamine is involved in a variety of different physiologicalfunctions, including but not limited to, immune and allegoric responses,endocrine system function and homeostasis as well as cell proliferation,differentiation hematopoiesis, embryonic development, regeneration,wound healing, aminergic neurotransmission, various other brainfunctions (sleep, nociception, food intake and aggressive behavior),secretion of pituitary hormones, regulation of gastrointestinal andcardiovascular systems, and other various signaling pathways. Histaminehas also been correlated with allergies (e.g., drug allergies, hayfever, allergic asthma, etc.). Elevated histamine has also been detectedin skin and plasma samples from patients with atopic dermatitis (AD),chronic urticaria (CU), multiple sclerosis (MS) and/or psoriatic skin.In Parkinson's Disease patients, histamine levels have been shown to beincreased in specific brain regions, such as the putamen, substantianigra and external globus pallidus. In Alzheimer's disease, certainhistaminergic neurons display degeneration and tangle formation. Also, adecline in histamine levels and/or HDC activity has been associated withAlzheimer's disease and Down's syndrome.

Histamine is synthesized by a variety of cells, including, but notlimited to mast cells, basophils, platelets, histaminergic neurons, andenterochromaffin cells. The activity of HDC is modulated by variouscytokines, including inflammatory cytokines such as interleukin (IL)-1,IL-3, IL-12, IL-18 and tumor necrosis factor (TNF). Histamine is storedintracellularly in vesicles and released by particular stimuli, such asstress, circadian rhythms, drugs and allergens. Mast cells arerelatively widely distributed throughout the body and the populationdensity of mast cells is very high in anatomical sites which interfacewith the external environment (e.g., skin, airways, and gastrointestinaltract) as well as regions in close proximity to blood vessels, nerves,smooth muscle cells, epithelial cells, mucus producing cells and hairfollicles. Given that histamine is stored in granules in a “ready torelease” fashion, substantial amounts of preformed histamine can bereleased in response to a single stimulus, and a multitude of varioustriggers can elicit large-scale and rapid-onset histamine release (e.g.,via mast cell degranulation), mast cells are a major cellular source ofhistamine. For example, in allergic reactions, for example, histamine isreleased from basophils and/or mast cells in response to particularallergens. Histamine mediates numerous biologic reactions, such as, forexample, immune responses (e.g., inflammatory reactions, modulation ofthe immune response) and the degranulation of mast cells after theirrecognition of specific allergens. Histamine-induced signaling alsoplays a role in responses to many other nonimmunologic stimuli, such as,for example, neuropeptides, complement factors, cytokines,hyperosmolarity, lipoproteins, adenosine, superoxidases, hypoxia,reactions with certain drugs, peptides, venom, and/or other“liberators”, physical insults (such as, for example, thermal,vibratory, radiant, or exertion), stressors (such as, for example,chemical, thermal, traumatic, or osmotic stressors), alcohol and certainfood and drugs that may activate mast cells, and/or spontaneous basophilrelease (which occurs with higher frequency in atopic individuals).Allergic reactions such as, for example, excessive sneezing, arepotentiated by the activation of histamine-based pathways becausehistamine also dilates blood vessels and increases permeability ofvessel walls, thereby allowing potentially greater influx of allergens.FIG. 2 (reproduced with permission from Maintz, et al., Histamine andHistamine Intolerance, The American Journal of clinical Nutrition, Vol.85: 1185-1196 (2007)) depicts the variety of different pathways in whichhistamine signaling plays a role, and examples of symptoms that mayarise from dysregulation of histamine. As a result of the multitude oftissues in which histamine signaling occurs, dysregulation of histaminefunction can present with confounding symptoms (e.g., those notnecessarily directly associated with a particular organ system, forexample vertigo as a result of histamine dysregulation in thecardiovascular system). As such, several embodiments of the methods andcompositions (and uses thereof) disclosed herein for restoration ofhistamine balance are particularly useful for amelioration (orelimination) of symptoms of histamine dysregulation in one or moretissues or tissue types.

Certain individuals are either sensitized to, or intolerant of,histamine. As discussed above, histamine is produced from L-histidine.Imbalance in the accumulation (e.g., production) and reduction (e.g.,degradation and/or metabolism) can lead to the sensitization and orintolerance to histamine. The primary enzyme for metabolism of ingestedhistamine is diamine oxidase (DAO). Reduced histamine degradation basedon insufficient DAO activity and can result in excess histamine and maycause symptoms mimicking allergic reactions. DAO is located in plasmamembrane-associated vesicular structures and is secreted into thebloodstream after stimulation. The second major enzyme for metabolism ofhistamine is histamine-N-methyltransferase (HNMT), which is a cytosolicprotein, and is therefore only capable of metabolizing intracellularhistamine. Notwithstanding their differing, and seeminglynon-competitive locations, reduced function of one or both of theenzymes can lead to histamine imbalance and/or sensitization to orintolerance of histamine. As discussed above, such imbalances can leadto a variety of adverse physiological consequences, and severalembodiments of the methods disclosed herein restore histamine balancethrough the administration of a therapeutic agent (e.g., histamine).

Endogenous histamine acts on a large variety of different cell typesincluding smooth muscle, neurons, endocrine and exocrine cells, bloodcells and cells of the immune system. Histamine exerts its multiplebiological actions via one of several receptors including the H1receptor (H1R), H2 receptor (H2R), H3 receptor (H3R) and more recently,H4 receptors (H4R). Each of the receptors is a G protein coupledreceptor, though they operate through various G-protein subunits and aredifferentially expressed in various cell types. The receptors have beendetected in various tissues, including but not limited to, mammalianbrain, respiratory tract, genito-urinary system and vascular system, aswell as on several types of leukocytes and hematopoietic cells. The H1receptors are mainly involved in the regulation of vascular permeabilityand smooth muscle contraction. The H2 receptor stimulation evokes anincrease of gastric acid secretion, an increase in mucus secretion inthe bronchi and the relaxation of smooth muscles of small blood vessels.The H3 receptors are classified as presynaptic receptors controllingneurotransmission in the central nervous system. H4 receptor signalingappears to modulate immune system processes and inflammatory reactions.It is believed that the principal receptors throughout the body are theH1 and H2 receptors, while H3 and H4 receptors have somewhat morelocalized expression profiles. In some instances, histamine signalingthrough H1R and/or H2R mediates excitation and long-term potentiation ofexcitation. In contrast, the H3R autoreceptors provide feedback controlof histamine synthesis, release, and electrical activity. Asheteroreceptors histamine receptors also function to control exocytosisof several other neurotransmitter systems (e.g., GABA, dopamine,serotonin, etc.). Histamine is also known to play a role in severalhomoeostatic and/or higher integrative brain functions (such asnovelty-induced attention (as opposed to voluntary attention) andadaptation to changing environments). While some overlap betweenfunction exists, the activity of the receptors can generally besummarized as in Table 1.

In several embodiments, histamine is provided in a multi-variableapproach, in which concentration, volume, and timing can be varied.Other variables can also be changed (such as infusion time, form ofhistamine, pH, etc.). In several embodiments, a multi-variablepharmacokinetic approach results in selective or enhanced activation ofcertain receptors. The affinities provided below are used in severalembodiments to induce specific and controlled histamine receptoractivation, which may in turn reduce or prevent many of the side-effectsassociated with programs that do not employ the approaches describedherein. These side-effects, which may result in non-compliance in takingthe therapy, can be avoided or reduced in many embodiments.

TABLE 1 Characteristics of Histamine Receptors G-protein Affinity forReceptor Function Expression Subunits Histamine H1 Smooth muscleNeurons, smooth Gαq/11 ~1.1 μg/mL contraction (most muscle muscle (e.g.,airways, other than vascular vascular), epithelial, smooth muscle);endothelial cells, vasodilation; increases in neutrophils, vascularpermeability eosinophils, monocytes, dendritic cells, T-cells, B cells,hepatocytes, and chondrocytes H2 Leukocyte function, Gastric mucosaparietal Gαs ~3.33 μg/mL gastric parietal cell cells, smooth-muscle,function (e.g., acid heart, epithelial, secretion), cardiac endothelialcells, stimulation neutrophils, eosinophils, monocytes, dendritic cells,T-cells, B cells, hepatocytes, and chondrocytes H3 Central NervousSystem Histaminergic neurons, Gi/o ~1.1 ng/mL neurotransmission; withrelatively low neurotransmission at expression elsewhere histaminergicperipheral nerve terminals H4 Hematopoietic and Bone marrow and Gi/o~2.2-4.4 ng/mL immunocompetent cell peripheral function hematopoieticcells, relatively low expression elsewhere

Histamine H1 Receptor

The distribution and occupancy of the histamine H1 receptor (H1R) inhumans has been mapped using functional imaging techniques to study thesedative properties and blood-brain barrier (BBB) permeability ofvarious H1R antihistamines. Similar studies have been performed in thecontext of aging and neuropsychiatric disorders, such as Alzheimer'sdisease, schizophrenia and depression. In most of these studies, H1Rbinding was found to be lower than in the age matched healthy controls,indicating that histamine imbalance, in several embodiments may becaused, at least in part by elevated H1 receptor expression. Of note isthat H1R stimulation has a feed-forward effect on H1R expression (e.g.,stimulation of the receptor induces up-regulation in receptorexpression). Histamine-induced up-regulation of H1 receptor expressionis thought to be mediated by protein kinase C-δ signaling. Mappingstudies have also identified a correlation between appearance of variousdisease symptoms and detection of increased histamine H1 receptor mRNA,as well as a strong correlation between H1R and allergic responses (orresponses to antihistamines used to treat allergy). For example, drugsfor treatment of allergic symptoms (e.g., antihistamines) not onlyreduce IL-4 and/or Il-5 expression but also H1 receptor gene expression.Histamine activation of the H1R leads to the release of the severalneurotransmitters (e.g., serotonin, dopamine and norepinephrine) andexcitation of neurons in most brain regions, including, but not limitedto, brain stem, hypothalamus, thalamus, amygdala, septum, hippocampusand cortex. The H1R signals through one or more of, increased calciumsignaling, cyclic guanosine monophosphate (cGMP) mediated signaling,nuclear factor κB (NF-κB), increased phospholipase C (PLC) activity,increased phospholipase A2 and/or D activity, cyclic adenosinemonophosphate activity (cAMP) and/or nitric oxide synthase activity, andthus can set in motion an enormous variety of signaling cascadesassociated with these pathways, such as, for example, as cellproliferation, cell differentiation, apoptosis, cytoskeleton remodeling,vesicular trafficking, ion channel conductance, endocrine function andneurotransmission. See FIG. 3 for a schematic representation ofhistamine receptor signaling.

Histamine H2 Receptor

The activation of H2R regulates various functions of histamine includingheart contraction, gastric acid secretion, cell proliferation,differentiation and immune response. In the brain, the highest densitiesof H2R are found in the basal ganglia, hippocampus, amygdale andcerebral cortex, with lower expression in cerebellum and hypothalamus.H2R stimulates accumulation of cAMP in a variety of tissue includinggastric cells, cardiac tissue and brain. In contrast to H1R, activationof H2R is mostly involved in suppressive activities of histamine. Forexample, it has been demonstrated that H2R activity can inhibit avariety of functions within the immune system and that H2R activitynegatively regulates release of histamine in basophils and mast cell.H2R-based inhibition of antibody synthesis, T-cell proliferation, cellmediated cytolysis, and cytokine production is further evidence of H2Rpresence on lymphocytes, and its negative (e.g., suppressive) effects onhistamine.

Histamine H3 Receptor

As indicated above, H3 receptors are primarily expressed in the centralnervous system, particularly on histaminergic neurons. H3 receptorscouple to Gi/o subunits to inhibit the function of adenylate cyclase andtherefore inhibition of cAMP formation, along with accumulation ofcalcium and stimulation of mitogen-activated protein kinase (MAPK)pathways. H3Rs also mediate synthesis of histamine and their activationleads to inhibition of histamine release from histaminergic neurons.Thus, in several embodiments, preferential stimulation of H3R cancounteract activity of the H1R (and thus reducing the feed-forwardincrease in H1R expression), thereby facilitating restoration ofhistamine balance. Conversely, H3 receptor blockers may enhance therelease of neurotransmitters. Also, activation of H3 receptors leads toinhibitory effects on many neuronal synapses that are non-histaminergic,including, but not limited to those signaling through glutamate,acetylcholine, dopamine, noradrenaline, serotonin, GABA and variouspeptides.

Histaminergic dysregulation has been found in a variety of different CNSdisorders and, as such, various H3 ligands have been investigated forclinical utility in CNS disorders, such as obesity, memory disorders,learning deficit and epilepsy. Additionally, loss of H3R function hasbeen associated with behavioral abnormalities, reduced locomotion, ametabolic syndrome with hyperphagia, late-onset obesity, increasedinsulin and leptin levels and an increased severity of neuroinflammatorydiseases. In several embodiments, the pharmacological properties of theH3R are advantageously exploited in the methods disclosed herein torestore histamine balance/function.

Histamine H4 Receptor

The H4 receptor is involved in cellular mechanisms related to immunesystems, inflammatory processes, and allergic reactions. As discussedabove, H4 receptors are expressed in bone marrow, spleen, peripheralblood, small intestine, heart, colon, lung, as well as hematopoieticcells, neutrophils, mast cells, eosinophils, basophils, monocytes, Tcells and dendritic cells. The H4R mediates eosinophil shape change andmast cell chemotaxis as a result of the βγ subunits acting onphospholipase C, which leads to calcium release, subsequent actinpolymerisation and eventually chemotaxis of the mast cells to a site ofinflammation.

Histamine Imbalance and Methods of Histamine Receptor Modulation

Normal serum histamine levels (e.g., levels in otherwise healthysubjects without an allergic event) range from about 40 to about 55ng/mL. Thus, in several embodiments, the rebalancing of the histaminesystem normalizes the serum histamine level to 40 to about 55 ng/mL. Inother embodiments, the rebalancing of the histamine system normalizesthe serum histamine level by decreasing or increasing histamine levelsby about 30%-70% with respect to baseline. As an example, and as furtherdiscussed below, normalizing histamine for a migraine sufferer may bereducing histamine from 120 ng/mL to 70 ng/mL. As discussed above, acondition of low histamine is referred to as histapenia, and a personhaving low histamine levels is referred to as “histapenic.” A conditionof high histamine is known as histadelia, and a person having highhistamine levels is referred to as histadelic.

Indications for Histamine Therapy

Various ailments and/or illnesses may be caused by, exacerbated by, orlinked with an imbalance in the levels of histamine and/or thefunctionality of the various histamine receptors. As discussed above,normal serum histamine levels range from about 40 to about 55 ng/mL.Histamine levels are imbalanced (e.g., higher or lower than normal) insubjects with ailments or diseases including, but not limited tomigraine headaches, vascular headaches, Alzheimer's disease, Parkinson'sdisease, coronary disease, leukemia, epilepsy, obesity, schizophrenia,Attention-Deficit Hyperactivity Disorders, Huntington's disease,allergies, asthma, autism, Lou Gehrig's disease, atherosclerosis,dementia, addiction and compulsion, metabolic syndrome, rheumatoidarthritis, sleep disorders, alcoholism, substance abuse, cancer,malaria, HIV/AIDS, Central Nervous System (CNS) dysfunctions (e.g.,stress, anxiety, depression, movement disorders, anxiety/fear-relateddisorders, hyperalgesia and brain ischemia), pre-diabetes, diabetes,lupus, cardiac arrhythmias. For example, serum histamine levels inmigraine sufferers (who do not also suffer from allergies) during a painfree period can range from about 60 to about 74 ng/mL. Thus, the“normal” histamine levels for a migraine sufferer are elevated ascompared to non-migraine sufferers. Thus, migraine sufferers may beinclined to have a migraine episode because of this histamine imbalance.In migraine sufferers who do also suffer from allergies, the resting(e.g., pain free) serum concentrations can range from about 70 to about95 ng/mL, indicative of a further histamine imbalance (see FIG. 4).These histamine levels are further increased during actual migraineevents (see FIG. 5). As with many physiologic parameters, there may beindividual-to-individual variability in the concentrations of histamine,however, an imbalance as compared a specific individual's “normalhistamine” concentrations (as measured, for example, by serum and/orurine concentrations) can lead to and/or exacerbate various ailmentsand/or illnesses. Thus, in several embodiments, a histamine receptoractivator(s) is provided for use in the treatment of diseases (and/orsymptoms) that include but are not limited to migraine headaches,Parkinson's Disease (FIG. 6), Alzheimer's Disease (FIG. 7), coronarydisease (FIG. 8), leukemia (FIG. 9), amyotrophic lateral sclerosisand/or epilepsy. Also provided herein are histamine receptor activator(or activators) for use in the treatment of migraine headaches,Parkinson's Disease (FIG. 6), Alzheimer's Disease (FIG. 7), coronarydisease (FIG. 8), leukemia (FIG. 9), amyotrophic lateral sclerosis,epilepsy, histadelia and/or histapenia (or other ailments) in patientsshowing an elevated amount of circulating histamine as well as ailmentsin which patients show a reduced amount of circulating histamine. Thus,in several embodiments, the invention comprises a histamine receptoractivator for use in the treatment of migraine headaches, Parkinson'sDisease, Alzheimer's Disease, coronary disease, leukemia, amyotrophiclateral sclerosis, epilepsy, histadelia and/or histapenia and isassociated with restoration of histamine balance in the subject. Inseveral embodiments, the invention comprises histamine receptoractivator for use in the treatment of diseases associated with theover-expression and/or over-activity of the histamine H1 receptor, or ahistamine receptor activator for use in the treatment of diseasesassociated with the under-expression and/or under-activity one or moreof the histamine H2, H3, and/or H4 receptors.

Histamine Therapy for Migraine Headache

Although embodiments disclosed herein are non-limiting and areapplicable to several neurological and other conditions, manyembodiments are especially useful for migraines. As discussed above,histamine imbalance is common in migraine headache sufferers. Migraineheadaches affect more than 30 million people in the United States alone.Roughly 25% of women and 9% of men experience migraine headaches whichresults in an average of 4 to 6 working days lost each year. In total,this results in an annual loss (nationwide) of between about 64 to 150million workdays, in turn, equating to direct and indirect costs ofnearly $50 billion in the United States alone (according to The NationalHeadache Foundation; see also, J D Bartleson, Treatment of MigraineHeadaches, Mayo Clin. Proc. 1999; 74; 702-708). Headache and associatedsymptoms are responsible for approximately 2% of all visits to emergencydepartments. Migraine headaches are generally described as recurring,unilateral headache with untreated symptoms lasting from 4 to 72 hours.The international headache Society Classification of headaches lists thepresence of at least two of the following symptoms for a headache to beconsidered a migraine headache: unilateral location, throbbingcharacter, worsening pain with routine activity, and moderate to severeintensity coupled with at least one of the following features: nauseaand/or vomiting and photophobia and phonophobia.

At present, there is no known cure for migraine headaches. Migrainetreatments are broadly classified as non-pharmacologic or pharmacologictreatments. While several embodiments disclosed herein are related topharmacologic methods (e.g., administration of a therapeutic agent, suchas histamine) to restore histamine balance and treat migraine headaches,in some embodiments, non-pharmacologic and/or combinations ofpharmacologic and non-pharmacologic methods are used.

Non-pharmacologic treatments typically involve targeting and/oravoidance of actions and behaviors known to trigger migraine headaches.For example, the non-pharmacologic treatments may include, in severalembodiments, regular sleep patterns, routine exercise, avoidance ofknown triggers. Depending on the individual migraine sufferer, triggerscan vary. Food triggers, depending on the embodiment include, but arenot limited to ripened cheeses (e.g., cheddar, Emmentaler, Stilton,Brie, and Camembert), chocolate, marinated, pickled, or fermented food,foods that contain nitrites or nitrates (e.g., bacon, hot dogs, delimeats) or MSG (e.g., soy sauce, meat tenderizers, seasoned salt), sourcream, nuts, peanut butter, sourdough bread, various legumes (e.g.,broad beans, lima beans, fava beans, snow peas), figs, raisins, papayas,avocados, red plums, citrus fruits, caffeinated beverages such as tea,coffee, or cola, and/or alcoholic beverages. For women, the menstrualcycle may be a trigger, perhaps related to changes in estrogen levels.Light intensity, light patterns (e.g., flickering lights) can also serveas triggers. Stress (e.g., anxiety, worry, shock, sadness, etc.) canalso be triggers, as it may set into motion signaling cascades thatinduce histamine imbalance. Strong odors (e.g., perfumes, chemicalodors, odors of certain cooked foods etc.) can also be triggers. Inseveral embodiments, triggers may change over time (e.g., a strong odormay be a trigger in once instance, but not in another). In severalembodiments, non-pharmacologic therapies also include, for example,relaxation training, biofeedback training, cognitive and/or behavioraltherapy, hypnosis, transcutaneous electrical nerve stimulation, cervicalmanipulation, and/or hyperbaric oxygen treatments. In severalembodiments, the therapeutic agent dosing regimens (e.g., histamine) aresupplemented with one or more non-pharmacologic treatments.

Pharmacologic treatments for migraine headaches can generally be dividedinto two main classes, namely abortive therapies and prophylactictherapies. As used herein, the term “abortive therapies” shall be givenits ordinary meaning and shall also refer to therapies that are act toreduce and/or ameliorate symptoms of a migraine that already exists. Inseveral embodiments, the abortive therapies can be furthersubcategorized into non-specific therapies and migraine specifictherapies. In several embodiments, the therapeutic agent dosing regimens(e.g., histamine) are supplemented with one or more pharmacologictreatments. Non-specific therapies that are optionally used in severalembodiments include, but are not limited to, for example,analgesics/NSAIDS (e.g., acetaminophen, aspirin, ibuprofen, naproxensodium, ketorolac), and narcotic analgesics (e.g., meperidine andbutorphanol), and adjunctive therapy (e.g., metoclopramide,prochlorperazine). Migraine specific abortive therapies that areoptionally used in several embodiments include, but are not limited toergotamine and/or ergotamine derivatives (e.g., ergotamine, caffeineplus ergotamine, dihydroergotamine) and the members of thetryptamine-based Triptans family (e.g., sumatriptan, naratriptan,rizatriptan, and zolmitriptan). Antihistamines are also used, in severalembodiments to preferentially and/or specifically target the activity ofcertain histamine receptors.

The term “prophylactic therapy” as used herein, shall be given itsordinary meaning and shall include therapies that prevent, avoid, limitand/or otherwise reduce the frequency and/or intensity of migraineheadaches. Prophylactic therapies are generally divided into thefirst-line agents and second-line agents. In several embodiments,first-line therapies for migraine prophylaxis in adults includepropranolol, timolol, amitriptyline, divalproex, sodium valproate,and/or topiramate. In several embodiments, second-line agents includeone or more of gabapentin, naproxen or naproxen sodium, timed-releasedihydroergotamine mesylate, candesartan, lisinopril, atenolol,metoprolol, nadolol, fluoxetine, verapamil, magnesium, vitamin B2(riboflavin), coenzyme Q10, hormone therapy (e.g., estradiol topicalgel), and botulinum toxin type A (Botox).

Many patients continue to experience migraine headaches despite optimaltherapy with the currently available therapies. However, in severalembodiments, restoration of histamine balance, as disclosed herein, andeither alone or in some embodiments, in combination withnon-pharmacologic and/or pharmacologic treatments, migraine suffererscan reduce, limit, prevent and/or lessen the frequency and/or intensityof migraine headaches.

In several embodiments, a therapeutic agent (e.g., histamine agonists orantagonists, naturally-occurring or synthetic) is administered to asubject who is a migraine sufferer, in order to establish circulatingconcentrations of the agent that result, in several embodiments, insuppression of the pro-migraine effects of histamine. In severalembodiments, the administration of the therapeutic agents (e.g.,histamine, or a synthetic histamine, or an agonist and/or antagonist)result in the concentration of selective interaction of the agents withH3R and/or H2R. As discussed above, activation of the H3R and/or H2R canreduce the synthesis and/or release of histamine, which in turn canreduce the expression of the H1R (due its activity induced increase inexpression), and thereby reduce the potential dominance of the H1R andrestore balance among the histamine receptors. The various histaminereceptors are thus specifically targeted by a histamine receptoractivator(s) for use in the treatment of migraine headaches, Parkinson'sDisease, Alzheimer's Disease, coronary disease, leukemia, amyotrophiclateral sclerosis, epilepsy, histadelia and/or histapenia, and otherdisorders.

Previous studies have been directed towards histamine administrationregimens. For example, during a controlled, double-blinded, clinicaltrial for migraine prevention, histamine was administered, twice a weekand for 12 weeks, in consecutively increasing subcutaneous doses (0.1 to1 ng) to compare efficacy of histamine versus to placebo for prophylaxisof migraine. See Guerrero R O, et al., Histamine as a therapeuticalternative in migraine prophylaxis: a randomized, placebo-controlled,double-blind study, Headache, Vol. 39(8): 576-80 (1999).

In another study, N^(α)-methylhistamine was administered at doses of 1to 3 ng twice a week, which significantly reduced (P<0.0001) thefrequency, intensity, and duration of migraine attacks, as well as theneed for rescue analgesics. However, at doses greater than 3 ng,patients experienced adverse side effects manifest as intense headache.See Millan-Guerrero R O, et al., N^(α)-Methylhistamine Safety andEfficacy in Migraine Prophylaxis: Phase I and Phase II Studies, HeadacheVol. 43:389-394 (2003) and Millan-Guerrero R O, et al., Nα-MethylHistamine Safety and Efficacy in Migraine Prophylaxis: Phase III StudyCan. J. Neurol. Sci., Vol. 33: 195-199 (2006).

In another comparative study, subcutaneous histamine (10 μg/mL in Evan'ssolution) was administered twice weekly, with an initial administrationof 1 μg (0.1 mL) and gradually increasing dose to 10 μg (1.0 mL) over a12-week period. Histamine was compared to placebo, sodium valproate, andtopiramate administration. The histamine group reported a reduction ofheadache frequency (50%), decrease in pain intensity (51%), length ofmigraine attacks (45%) and painkiller use (52%). See Millan-Guerreroa RO, et al., Nueva alternativa terapéutica en profilaxis de migraña conhistamina como agonista de receptores H3 Gac Méd Méx Vol. 144 No. 4:291-295 (2008).

Histamine was also compared to sodium valproate in a 12-weekdouble-blind controlled clinical trial. Subcutaneous administration ofhistamine (1-10 ng twice a week) was compared with oral administrationof sodium valproate (500 mg daily dose). Data collected during the 4th,8th and 12th weeks of treatment revealed that histamine caused asignificantly greater reduction (P<0.001) in intensity and duration ofmigraine attacks as well as in analgesic intake. No difference wasdetected in the frequency of attacks or in MIDAS. See Milian-Guerreroa RO, et al., Subcutaneous histamine versus sodium valproate randomized,controlled, double-blind study European Journal of Neurology, Vol. 14:1079-1084 (2007). A similar trial compared subcutaneous administrationof histamine (1-10 ng twice a week) with oral administration oftopiramate (100 mg daily dose). See Millan-Guerreroa R O, et al.,Subcutaneous Histamine versus Topiramate in Migraine Prophylaxis: ADouble-Blind Study, Eur Neurol; Vol. 59:237- 242 (2008). An additionaltrial compared histamine (subcutaneous, 1-10 ng, twice per week) withBotox injection (50 Units, one injection cycle). See Millan-Guerrero RO, et al., Subcutaneous histamine versus botulinum toxin type A inmigraine prophylaxis: a randomized, double-blind study, European Journalof Neurology, Vol. 16: 88-94 (2009).

Additional studies have shown that in migraine subjects, intravenousadministration of relatively high doses of histamine (e.g., 0.5 mg/kgper minute for 20 min) caused an immediate headache during the infusion,followed by a delayed migraine attack. Those side effects couldabolished by pre-treatment with the H1R antagonist mepyramine. SeeKrabbe and Olesen (Krabbe A A, 1980) and Lassen et al. (Lassen L H,1995).

Other studies report methods of determining histamine dosing regimens.One such approach is empiric optimum dosing while another is objectiveendpoint titration. Empiric optimum dosing involves injection ofhistamine with a particular frequency (e.g.,) once or twice a week toinitiate treatment in conjunction with supplementation by dailysublingual drops. The dose of histamine is increased to the point ofoptimum clinical response, but short of aggravation. An objectiveendpoint titration approach involves determining the dose of histaminethat induces an allergic response (e.g., successively more concentratedintracutaneous doses are administered until an allergic wheal results).That dose is defined as the treatment dose, and subcutaneous injectionsof that dose are administered at a declining frequency.

In spite of ongoing histamine research and uses of histamine in varioustherapeutic contexts, there remains a need for histamine dosing regimensthat are capable of restoring the body's natural histamine function, andthat can treat disease states caused by imbalances in the body's releaseand metabolism of histamine, such as, for example, migraine headache.Additionally, therapeutic benefit may not be realized by subjects whoare treated with therapies in accordance to the studies discussed above,and/or such therapeutic benefit may be associated with side effects.Moreover, in contrast to the methods disclosed herein, many currentattempted therapeutic uses of histamine do not account for the selectiveactivation of specific histamine receptors (several embodiments of thedisclosed methods are based on the exploitation of the differingpharmacological characteristics of the histamine receptors), whichunexpectedly provides exceptional therapeutic results and treatments forhistapenia, histadelia, and/or disorders that are related to orassociated with histamine imbalance.

Thus, several embodiments of the invention provide an escalating dosingregimen comprising in sequential order (a) a first dosing segmentcomprising two or more sequential doses of a therapeutic agent (e.g.,histamine, or a salt thereof, such as, for example, histamine phosphateor histamine dihydrochloride) separated by one or more equal timeintervals (the “first time interval”), wherein the concentration of theagent is increased from dose to dose while the administered volume ofeach dose stays constant; and (b) a second dosing segment comprising twoor more sequential doses of the therapeutic agent separated by one ormore equal time intervals (the “second time interval”), wherein theconcentration of the agent increases from dose to dose while theadministered volume of each dose stays constant; wherein the volume ofeach dose in the second dosing segment is greater than the volume ofeach dose in the first dosing segment, and the second time interval islonger than the first time interval.

As used herein, the terms “first” and “second” are used in relation toone another, and not to the overall dosing regimen. Thus, the dosingregimen can comprise more than two dosing segments, in which case thefirst dosing segment can refer to any dosing segment within the dosingregimen other than the last dosing segment, and the second dosingsegment can refer to any dosing segment performed after the first dosingsegment. Depending on the embodiment, the regimen may comprise 2, 3, 4,5, 6, 7, 8, 9, 10 or more total dosing segments. Thus, the first dosingsegments can be any of segments 1 through 9, while the second dosingsegment can be any succeeding dosing segment 2 through 10.

In several embodiments, the dosing regimen is a fixed regimen, in thatthe complete regimen is administered to the patient in order to achieveoptimal therapeutic benefits (e.g., if the regimen is 10 segments, thenall 10 segments are completed). However, in several embodiments, theregimen is optionally truncated for one or more of a variety of reasons.In several embodiments, the regimen is truncated because the patientreceived the regimen has experienced a sufficient therapeutic benefit.For example, in several embodiments directed to migraine treatment, thesubject may have experienced a significant reduction in pain, frequency,duration, and/or intensity of migraine episodes. In several embodiments,the subject can restart a regimen after a given period of time, forexample several days to several months, including about 2 to about 7days, about 7 to about 14 days, about 14 to about 21 days, about 21 daysto about 4 weeks, about 4 weeks to about 8 weeks, about 8 weeks to about12 weeks, and overlapping ranges thereof. A subject may restart aregimen at the point that the regimen was optionally truncated (e.g.,picking up where the subject left off). The regimen may also berestarted from the point of inception (e.g., dose #1 of segment #1).Restarting the regimen may be due to a reduction in the benefits fromthe prior administration of the regimen (e.g., return of symptoms and/orincrease in, for example, migraine frequency). While several embodimentsof the methods disclosed herein are surprisingly without side effects(e.g., in some segments, the doses of histamine exceed those that havecaused side effects in other studies, but do not induce side effectssuch as migraines), in several embodiments, the regimen is optionallytruncated due to side effects. Depending on the clinical conditions, theregimen can be cut short either by stopping at a particular dosingvolume within a dosing segment, or by stopping before performing asucceeding segment. In several embodiments, rather than a truncation, asubject can maintain a particular segment of the regimen for one or moretime periods (e.g., repeat segment #4 for a plurality of timeintervals), or repeat a previously administered segment one or moretimes (e.g., rather than administer segment #4, re-administer segment #3for one or more time periods).

In several embodiments, the number of doses administered during thefirst dosing segment is equal to the number of doses administered duringthe second dosing segment. In several embodiments, one or all of thesegments can comprise 2, 3, 4, 5, 6, 7, 8 or more doses. In severalembodiments, four individual doses are given in the first dosingsegment. In several embodiments, subsequent dosing segments have fourindividual doses. In some embodiments, the number of doses is greater orlesser, depending on the needs and clinical symptoms of a given patient.For example, in several embodiments 2-3, 3-4, 4-8, 8-12, or 12-24 (andoverlapping ranges thereof) doses are administered within a given dosingsegment. Each dosing segment can comprise a different number of dosesalthough, as noted above, in several embodiments, each segmentpreferably includes the same number of doses.

Additionally, in several embodiments, the first dosing segment and thesecond dosing segment are separated by a first time interval. In severalembodiments, the time interval ranges from about 3 to about 30 days,including about 3 to about 5, about 5 to about 7, about 7 to about 10,about 10 to about 15, about 15 to about 20, about 20 to about 25, about25 to about 30 days, and overlapping ranges thereof. As discussedherein, in certain embodiments, the time interval varies between, forexample the first and second segments, as compared to, for example, thefourth and fifth segments. In several embodiments, the time interval isdetermined by a subject's responsiveness (or refractoriness) to a dosingsegment. In additional embodiments, the dosing segment interval isdetermined by other variables, such as for example, convenience orpersonal preference of the subject. In several embodiments, the firstdosing segment is optionally administered on a compressed time-frame.For example, in several embodiments the doses comprising the firsttherapy segment are, in several embodiments, administered within ashortened time frame 1-2 minutes, about 2-3 minutes, about 3-4 minutes,about 4-5 minutes, about 5-10 minutes, about 10-20 minutes, about 20-30minutes, and overlapping ranges thereof. In several embodiments, thefirst therapy segment comprises simultaneously delivery of each of thedoses within the segment. As a result, the modulation of the variousreceptors occurs on a reduced time-frame, and in some embodiments,simultaneously.

In several embodiments, the dosing regimen further comprises at least athird dosing segment comprising two or more sequential doses of thetherapeutic agent (e.g., histamine) separated by one or more equal timeintervals (the “third time interval”). In several embodiments, theconcentration of the agent increases from dose to dose while theadministered volume of each dose within the segment stays constant, andthe volume of each dose in the third dosing segment is greater than thevolume of each dose administered in the second dosing segment. Further,in several embodiments the third time interval is longer than the secondtime interval (though, in some embodiments, the time interval canoptionally be altered to be equivalent to, or shorter than, the timeinterval of a preceding dosing segment). This third dosing segment canbe any segment that follows the second segment in a multiple segmentregimen.

In several embodiments comprising at least three administrationsegments, (i) the concentrations of the therapeutic agent (e.g.,histamine, such as histamine phosphate or histamine dihydrochloride)administered during the third dosing segment are the same as theconcentrations of the therapeutic agent (e.g., histamine, such ashistamine phosphate or histamine dihydrochloride) administered duringthe second dosing segment; (ii) the number of doses administered duringthe third dosing segment is equal to the number of doses administeredduring the second dosing segment; and (iii) the second dosing segmentand the third dosing segment are separated by the second time interval.

In some embodiments, the dosing regimen comprises up to 10 sequentialdosing segments, wherein (a) each dosing segment comprises two or moresequential doses of the therapeutic agent (e.g., histamine) separated byone or more equal time intervals, (b) concentration of the agentincreases from dose to dose while the administered volume of each dosestays constant; (c) the volume of each dose in a succeeding dosingsegment is greater than the volume of each dose in the preceding dosingsegment; (d) the time interval in each succeeding dosing segment islonger than the time interval in the preceding dosing segment; (e) theconcentrations of the agent administered are the same in each dosingsegment; (f) the number of doses administered during each segment isequal; and (g) each succeeding dosing segment is separate from theimmediately preceding dosing segment by the time interval observed forthe immediately preceding dosing segment.

As discussed above, in several embodiments, the individual doses withina segment are given in a constant volume. For example, in severalembodiments, the first dosing segment comprises a plurality ofindividual doses, each administered in a volume of between about 0.01 toabout 1.0 mL, including about 0.01 mL to about 0.05 mL, about 0.05 mL toabout 0.10 mL, about 0.10 mL to about 0.15 mL, about 0.15 mL to about0.20 mL, about 0.20 mL to about 0.50 mL, about 0.50 mL to about 0.75 mL,about 0.75 mL to about 1.0 mL, and overlapping volumes therebetween. Inseveral embodiments, the volume of therapeutic agent (e.g., histamine)administered in each subsequent segment is greater than the volume ofthe therapeutic agent administered in the immediately preceding segment.For example, if the volume of the therapeutic agent administered in afirst segment is 0.1 mL, the volume of the therapeutic agentadministered in the next segment is greater than 0.1 mL. In severalembodiments, the volume of the therapeutic agent administered in a givendosing segment is 0.1 ml greater than the previous segment. In severalembodiments, the volume of the therapeutic agent administered in thelast segment ranges from about 0.1 to about 10 mL, including about 0.1mL to about 1.0 mL, about 1.0 mL to about 2.0 mL, about 2.0 mL to about5.0 mL, about 5.0 mL to about 7.5 mL, about 7.5 mL to about 10.0 mL, andoverlapping volumes therebetween. In several embodiments, the volume ofthe therapeutic agent administered in the last segment is about 1.0 mL.

In several embodiments, the concentration of the therapeutic agent(e.g., histamine) administered within each segment increases with eachindividual dose. For example, in the first (e.g., the starting) segment,the concentration of the therapeutic agent can range from about 0.1attogram/mL to about 10 μg/mL, including about 0.1 attogram/mL to about1 attogram/mL, about 1 attogram/mL to about 1 femtogram/mL, about 1femtogram/mL to about 1 picogram/mL (pg/mL), about 1 pg/mL to about 100pg/mL, about 100 pg/mL to about 200 pg/mL, about 200 pg/mL to about 300pg/mL, about 300 pg/mL to about 400 pg/mL, about 400 pg/mL to about 500pg/mL, about 500 pg/mL to about 600 pg/mL, about 600 pg/mL to about 700pg/mL, about 700 pg/mL to about 800 pg/mL, about 800 pg/mL to about 900pg/mL, about 900 pg/mL to about 1 ng/mL, about 1 ng/mL to about 5 μg/mL,about 0.1 μg/mL to about 3 μg/mL, and overlapping ranges thereof. Inseveral embodiments, the next dose is greater than the immediatelypreceding dose. In several embodiments, the final dose in a segmentranges from about 0.1 μg/mL to about 20 μg/mL, including from about 1μg/mL to about 2 μg/mL, about 2 μg/mL to about 3 μg/mL, about 3 μg/mL toabout 3.5 μg/mL, about 3.5 μg/mL to about 4 μg/mL, about 4 μg/mL toabout 6 μg/mL, about 6 μg/mL to about 8 μg/mL, about 8 μg/mL to about 10μg/mL, and overlapping ranges thereof. Thus, the concentrations from theinitial dose within a segment to the final dose within a segment rangefrom about 0.1 attogram/mL to about 20 μg/mL, from about 1 pg/mL toabout 1 ng/mL, from about 1 ng/mL to about 1 μg/mL, from about 1 μg/mLto about 3.5 μg/mL, from about 3.5 μg/mL to about 15 μg/mL, from about15 μg/mL to about 20 μg/mL, and overlapping ranges thereof. In someembodiments, the ratio of total amounts given in each therapy segment is1:2:3 (for three segments), 1:2:3:4 (for four segments), 1:2:3:4:5 (forfive segments). In some embodiments, the ratio of individual doseswithin in a given therapy segment is 1:10³:10⁶:3.5×10⁶. Theconcentrations of the therapeutic agents (e.g., histamine) providedherein can be the dose administered to the subject, or in certainembodiments, the plasma concentration achieved.

In several embodiments, the overall dose for a segment (e.g., the totalquantity of a therapeutic agent, such as histamine, administered in eachdose within a segment) preferably falls with the following ranges:

-   -   Segment 1        -   Initial Dose: about 0.1 attogram to about 1 ng, or about 100            attograms to about 10 pg        -   Concluding Dose: about 1 ng to about 1 μg, or about 100 ng            to about 500 ng    -   Segment 2        -   Initial Dose: about 1000 attograms to about 1 ng, or about            0.1 pg to about 100 pg        -   Concluding Dose: about 10 ng to about 10 μg, or about 1 μg            to about 5 μg

More specifically, in several embodiments, each individual dose within asegment is designed to target a specific histamine receptor (orreceptors), based on the affinity of the various receptors for histamine(see e.g. Table 1). For example, an initial dosing segment thatcomprises four doses, D1, D2, D3, and D4, with D1 being the lowestconcentration and D4 being the highest concentration would target,respectively H3/H4, H3/H4, H1, and H2. Further, as a non-limitingexample, in embodiments in which histamine is administered, the totalamount of histamine administered in D1 ranges from about from about0.0001 pg to about 999 pg, the total amount of histamine administered inD2 ranges from about from about 1 ng to about 999 ng, the total amountof histamine administered in D3 ranges from about from about 1 μg toabout 3.499 μg (for example about 1 μg to about 2.999 μg), and the totalamount of histamine administered in D4 ranges from about from about 3.0μg to about 10 μg (for example about 3.5 μg to about 10 μg). Asdiscussed above, and continuing the non-limiting example, a seconddosing segment comprising 4 doses, D5, D6, D7, and D8, which, in severalembodiments, are of a greater volume than the doses in the first dosingsegment, results in administration of greater amounts of histamine (notonly with respect to the corresponding dose in the previous segment, butalso with respect to the immediately preceding dose within the currentsegment, if any). Thus, for example, the total amount of histamineadministered in D5 ranges from about from about 0.0002 pg to about 1998pg, the total amount of histamine administered in D6 ranges from aboutfrom about 2 ng to about 1998 ng, the total amount of histamineadministered in D7 ranges from about from about 2 μg to about 5.998 μg(for example about 2 μg to about 5.998 μg), and the total amount ofhistamine administered in D8 ranges from about from about 7.0 μg toabout 20 μg. In some embodiments, the ratio of total amounts given ineach therapy segment is 1:2:3 (for three segments), 1:2:3:4 (for foursegments), 1:2:3:4:5 (for five segments). In some embodiments, the ratioof individual doses within in a given therapy segment is1:10³:10⁶:3.5×10⁶.

As a further example of the targeting of a specific histamine receptor(or receptors) based on dose, timing of administration, concentration,etc. the concept of natural/resonant frequencies may be informative. Agiven object possesses a natural frequency at which it will vibrate uponexcitation. For example, a guitar string tuned to a specific pitch andplucked with a given force will vibrate at a natural frequency. Adifferent string tuned to a different pitch will vibrate at its ownnatural frequency. The measure of natural frequency depends on thecomposition of a particular object, its size, structure, weight andshape. If a vibrating force is applied to an object with the frequencyof the vibrating force equal to the natural frequency, a resonancecondition results. The histamine receptors can conceptually beanalogized to objects with differing resonant frequencies. For example,if the H1 receptor has a resonant frequency of X, the H2 receptor has aresonant frequency of Y, the H3 receptor has a resonant frequency of Z,and the H4 receptor has a resonant frequency of A, application of avibration force (e.g., a histamine concentration) at X, Y, Z, or A willresult in specific stimulation of one of the histamine receptor types.As a further example, consider three blocks (one for H1 receptors, onefor H2 receptors, and one for H3 receptors), each with a differentnatural frequency. Application of a vibration force (e.g., a histamineconcentration) at or near the natural frequency of the block (e.g., theconcentration at which histamine activates the specific receptor type)will cause resonant frequency movement of that block (e.g., receptoractivation) while the other blocks, although perhaps moving, are not attheir resonant frequencies (e.g., the receptors may have someactivation, but less than that of the peak activation resulting fromcertain concentrations of histamine). Further, when a vibration forcegreater than the natural frequency of a block is applied, the block mayno longer respond or may respond to a lesser degree. However, anadditional block, that didn't respond to the first force, may respond tothe second force, if it approaches the natural frequency of the block.See also, for example the video athttp://www.youtube.com/watch?v=LV_UuzEznHs (by Professor O. Kwan,Department of Civil Engineering, University of Toronto; videoincorporated by reference herein). Further in several embodiments, theblocks (e.g., various histamine receptors) may respond at differentharmonics, multiples of the resonant frequency (e.g., multiples orfractions of a histamine concentration that causes receptor activation).As discussed in more detail herein, not all histamine concentrationsproduce the same effect on the histamine receptors (H1R-H4R) andexciting a specific histamine receptor at a given histamineconcentration approximating its specific affinity for histamine, forcesthat specific receptor to “resonate”, resulting in increased specificreceptor activation.

Depending on the embodiment, the duration of each dosing segment canvary. In several embodiments, the duration of the segment ranges fromabout one day to about one week, including about 1 to about 2 days,about 2 to about 4 days, about 4 days to about 6 days, about 5 days toabout 7 days, and overlapping ranges thereof. In several embodiments,the dosing segments range from about 1 week to about 16 weeks, includingabout 1 to about 2 weeks, about 2 to about 3 weeks, about 3 to about 4weeks, about 4 to about 6 weeks, about 6 to about 9 weeks, about 9 toabout 12 weeks, about 12 to about 16 weeks, and overlapping rangesthereof. In several embodiments, a subsequent dosing segment is longerin duration that it's immediately preceding dosing segment.

For example, in several embodiments, wherein a first dosing segment isabout 2 weeks, a second dosing segment is, for example, about 2 to about4 weeks in duration. In several embodiments, comprising additionalsegments, the duration of each segment continues to increase. In severalembodiments, a subsequent dosing segment is longer in duration than itsimmediately preceding dosing segment. Depending on the embodiment (e.g.,the duration of the dosing segment and the number of individual doseswithin a segment), the dosing frequency within a segment can range fromdaily dosing to dosing once every several weeks. In several embodiments,dosing within a segment occurs daily, every two days, every third day,every fifth day, once per week, twice per week, once every 10 days, onceevery two weeks, once every three weeks, once every month, once everysix weeks, and frequencies within those listed. In several embodiments,as the number of dosing segments increases, a subsequent dosing segmenthas a reduced dosing frequency as compared to its immediately precedingdosing segment. In several embodiments, a subsequent dosing segment notonly longer in duration than its immediately preceding dosing segment,the subsequent dosing segment has a reduced dosing frequency as comparedto its immediately preceding dosing segment. Table 2 depicts anon-limiting example of a dosing regimen in accordance with severalembodiments disclosed herein. In some embodiments, one or more segmentdurations are compressed by 50% to 99% (e.g., 60%, 75%, 85%, 90%, 95%).As a non-limiting example, the 4 steps of Segment 1 can be done in asingle day.

In several embodiments, the invention comprises a dosing regimen inwhich the volume, concentration, and/or timing of administration of atherapeutic agent (e.g., histamine or salt of histamine) is administeredvariably. Other approaches employ singular variability (e.g., changingonly one of concentration, volume, or timing). Advantageously, however,several embodiments of the methods employ such three-dimensionalvariability and result an unexpectedly more robust therapeutic effect.In several embodiments, the improved therapeutic effect is achievedwithout significant side effects. In several embodiments, the improvedefficacy is derived from the more specific histamine receptor targetingthat the varied concentrations for each dose achieve (e.g., theconcentrations of the various doses exploit the varied affinity of theH1R-H4R for histamine, or other therapeutic agent). In severalembodiments, the increase in volume from segment to segment allows agreater proportion of the histamine receptors in a given area to beactivated (or suppressed depending on the particular receptor and/or theamount of histamine given). The varied timing, in several embodiments,helps prevent receptor desensitization that could result if frequency ofadministration were constant over time. In such a case, an increaseddose would be administered at constant intervals, which could result inone or more of the histamine receptors becoming refractory to thehistamine, particularly in view of the increased dose from segment tosegment. Thus, as a subject proceeds through the segments in a givenregimen, the variability in concentration, volume, and timing result ineffects on the various histamine receptors (e.g., upregulation ordownregulation in activity and/or expression) that result in restorationof histamine balance.

In several embodiments, dosing regimens in accordance with the methodsdisclosed herein (a non-limiting example of which is shown in Table 2)can be used to return patients histamine concentrations to optimumhistamine ranges, whether their histamine levels are above or below theoptimum (healthy population) histamine level (plasma or urine).Advantageously, depending on the embodiment, the concentration rangepresented in each step (for example Segment 1, Step Number 2) allows formultiple “sub-concentrations” to be implemented as part of the dosingregimen. For example, as discussed in more detail below, Table 3 shows anon-limiting embodiment where C1=1.1 ng/mL and C2 is 3 ng/mL.

In several embodiments, the methods enable the lowering of histaminelevels in a patient having a histamine level above a level required foroptimum histamine function (e.g., histadelia), comprising administeringhistamine (synthetic to natural), a histamine agonist or antagonist, ora pharmaceutically acceptable salt thereof to the patient according tothe dosing regimens disclosed herein. In several embodiments, themethods disclosed herein enable the increase of histamine levels in apatient having a histamine level below a level required for optimumhistamine function (e.g., histapenia), comprising administered histamine(synthetic to natural), a histamine agonist or antagonist, or apharmaceutically acceptable salt thereof to the patient according to thedosing regimens disclosed herein.

In several embodiments, there are also provided “combination” dosingregimens that are used to facilitate returning a patient's histamineconcentrations to within optimum ranges for that individual (e.g.,whether that particular patient's histamine levels are above or belowthe average of a healthy population. As with several other embodimentsdisclosed herein, the combination regimen enables the lowering ofhistamine levels in a patient having a histamine level above a levelrequired for optimum histamine function (e.g., histadelia). The methodcomprises, in several embodiments, administering histamine (synthetic ornatural), a histamine agonist or antagonist, or a pharmaceuticallyacceptable salt thereof to the patient according to the non-limitingdosing regimen shown in Table 3. In several embodiments, the combinationdosing regimen enables the increase of histamine levels in a patienthaving a histamine level below a level required for optimum histaminefunction (e.g., histapenia), the method comprising administeringhistamine (synthetic or natural), a histamine agonist or antagonist, ora pharmaceutically acceptable salt thereof to the patient according tothe non-limiting dosing regimen shown in Table 3.

In several embodiments, the combination regimen comprises a plurality(e.g., 2, 3, 4, 5, 6, or more) of initial segments, each comprising, forexample, four individual doses (although a greater number of doses mayoptionally be administered). As discussed in relation to otherembodiments disclosed herein, the concentration of each dose isincreased with respect to one another, but the volume administered isheld constant across a given dosing segment. In additional embodiments,one or more of the concentration or volume may also be varied, based onthe individual subject's needs and/or symptoms. In some embodiments, theinitial segments serve as a “loading period”, in that histamine isinitially administered in a reciprocating pattern. For example, segment1 of Table 3 comprises four doses, each increasing in concentrationrelative to one another. The first dose of segment 2, however, is lowerthan the final dose of segment 1. Thus the doses increase over a givensegment, then drop back to concentrations that are less than theconcentration of the last dose administered. This “two step forward, onestep back” approach enables the gradual manipulation of the varioushistamine receptors and a more gradual re-establishment of histaminelevels, which advantageously reduces risk of side effects. After theinitial segments have been administered, a “loading dose” of histamine(or agonist/antagonist, etc.) has been established and, advantageously,one or more of the individual doses can be eliminated in subsequentdosing segments. Therefore, in several embodiments, dosing regimens,such as the non-limiting embodiment of the dosing regimen shown in Table3, can be directed to only a portion of the histamine receptors. Forexample, the non-limiting embodiment of the dosing regimen shown inTable 3 is directed to the H1, H2, H3 and H4 receptors. In additionalembodiments, however, doses and/or volumes are adjusted to enabletargeting of, as an example, H1 and/or H2, and/or H3 receptors.Additionally, in some embodiments, dosing regimens target only twohistamine receptors. In such embodiments, the volumes and concentrationsare adjusted accordingly. For example, the non-limiting example dosingregimen in Table 3 could be adjusted to target H2 and H3 receptors or H2and H4 receptors.

Additionally, as shown in an additional non-limiting embodiment in Table3A, after dosing segment 3, each subsequent dosing segment comprises 3doses, with concentration 1 (C1) having been eliminated from the doses.In several embodiments, concentration 1 is eliminated because both C1and C2 are directed at the H3 and/or H4 receptors. Thus, multiple dosesdirected to these two receptors may, in several embodiments, induce arefractoriness to histamine (e.g., the H3 and/or H4 receptor may becomeless sensitive if over stimulated) or may induce a change in expression(e.g., a reduction or increase in gene, or protein, that would reducethe efficacy of doses targeting H3 and/or H4). Moreover, in severalembodiments, the use of a single dose targeting the H3 and/or H4receptors reduces risks of adverse side effects or sensitivity tohistamine (or an agonist or antagonist thereof, depending on theembodiment). Therefore, in several embodiments, dosing regimens, such asthe non-limiting embodiment of the dosing regimen shown in Table 3A, aredirected to only a portion of the histamine receptors. For example, thenon-limiting embodiment of the dosing regimen shown in Table 3A isdirected to the H1, H2 and H3 receptors. In additional embodiments,however, doses and/or volumes are adjusted to enable targeting of the H4receptor in addition to the H1, H2, and/or H3 receptors. Additionally,in some embodiments, dosing regimens target only two histaminereceptors. In such embodiments, the volumes and concentrations areadjusted accordingly. For example, the non-limiting example dosingregimen in Table 3A could be adjusted to target H2 and H3 receptors.

In several embodiments, the volumes are adjusted proportionately, suchthat, for example, segment 1 would comprise two concentrations (onetargeting each receptor) and volumes for each of 0.05 mL, therebyretaining the 0.1 mL total volume delivered. Likewise, the total volumefor Segment 2 would still add up to be 0.2 mL, but would be delivered in2 administration volumes of 0.1 mL (one for each concentration), and 0.3mL for Segment 3 (delivered in 2 administration volumes of 0.15 mL, onefor each concentration), and the like.

In several embodiments, as discussed above, doses can be administered ona compressed time scale, e.g., two, three, four (or more) dosesadministered within a few seconds, a few minutes, within an hour, withinseveral hours, etc. In several embodiments, this approach advantageouslyreduces risk of side effects, which is particularly beneficial forindividuals who are sensitive to histamine (or itsagonists/antagonists). Also, in several embodiments, such a dosingregimen increases compliance because, as shown in Table 3, after thefirst 3 segments, each subsequent segment not only comprises a smallernumber of doses, but each segment is also is administered on acompressed time frame. Thus, as an example, segment 4 is administeredall within a single day (e.g., May 13) and no additional doses need beadministered until 2 weeks later. The compressed dosing schedule is suchthat the entirety of a segment can be considered a single “dose” eventhough the various concentrations of histamine (or itsagonists/antagonists) are administered separately (within a time frameof several seconds, e.g., within about 5 seconds, within about 10seconds, within about 15 seconds, etc.). Additionally, as the segmentnumber increases, the duration between segments increases, and with thecompressed doses within each segment, the actual administration ofhistamine (or its agonist or antagonist) occurs within a very shortrelative period of time. As such, the treatment of histamine imbalanceneed not be an intrusion into the day to day lives of patients, but canbe addressed in a matter of moments, once every few weeks (or longer).Lastly, the segment sequence can be rearranged, depending on thecondition, in order to achieve optimum results.

TABLE 3 “Combination” Dosing Regimen for Histadelia and/or HistapeniaSegment Dose Concen- Administration Dosing Number Number tration VolumeDate Frequency 1 1 C1 0.1 mL February 4 2x/week 2 C2 0.1 mL February 7 3C3 0.1 mL February 11 4 C4 0.1 mL February 14 2 5 C1 0.2 mL February 181 x/week  6 C2 0.2 mL February 25 7 C3 0.2 mL March 4 8 C4 0.2 mL March11 3 9 C1 0.3 mL March 18 1 x/2 10 C2 0.3 mL April 1 weeks 11 C3 0.3 mLApril 15 12 C4 0.3 mL April 29 4 13 C1 0.1 mL May 13 2 weeks C2 0.1 mL(+/−1 C3 0.1 mL week) C4 0.1 mL 5 14 C1 0.15 mL June 3 3 weeks C2 0.15mL (+/−2 C3 0.15 mL weeks) C4 0.15 mL 6 15 C1 0.2 mL July 1 4 weeks C20.2 mL (+/−2 C3 0.2 mL weeks) C4 0.2 mL 7 16 C1 0.25 mL August 5 5 weeksC2 0.25 mL (+/−3 C3 0.25 mL weeks) C4 0.25 mL 8 17 C1 0.3 mL September 96 weeks C2 0.3 mL (+/−4 C3 0.3 mL weeks) C4 0.3 mL C1 = 1.1 ng/mL +/−30% histamine base C2 = 3 ng/mL +/− 50% histamine base C3 = 1.1 μg/mL+/− 30% histamine base C4 = 3.33 μg/mL +/− 30% histamine base

TABLE 3A “Combination” Dosing Regimen for Histadelia and/or HistapeniaSegment Dose Concentration/ Administration Dosing Number Number VolumeDate Frequency 1 1 C1/0.1 mL February 4 2x/week 2 C2/0.1 mL February 7 3C3/0.1 mL February 11 4 C4/0.1 mL February 14 2 5 C1/0.2 mL February 181x/week 6 C2/0.2 mL February 25 7 C3/0.2 mL March 4 8 C4/0.2 mL March 113 9 C1/0.3 mL March 18 1x/2 10 C2/0.3 mL April 1 weeks 11 C3/0.3 mLApril 15 12 C4/0.3 mL April 29 4 13 C2/0.1 mL May 13 2 weeks C3/0.1 mLC4/0.1 mL 5 14 C2/0.13 mL  June 3 3 weeks C3/0.13 mL  C4/0.13 mL  6 15C2/0.17 mL  July 1 4 weeks C3/0.17 mL  C4/0.17 mL  7 16 C2/0.2 mL August5 5 weeks C3/0.2 mL C4/0.2 mL 8 17 C2/0.23 mL  September 9 6 weeksC3/0.23 mL  C4/0.23 mL  9 18 C2/0.27 mL  October 28 7 weeks C3/0.27 mL C4/0.27 mL  10 19 C2/0.3 mL December 23 8 weeks C3/0.3 mL C4/0.3 mL 1120 C2/0.33 mL  February 24 9 weeks C3/0.33 mL  C4/0.33 mL  C1 = 1.0pg/mL histamine base C2 = 1.0 ng/mL histamine base C3 = 1.0 μg/mLhistamine base C4 = 3.5 μg/mL histamine base

The concentrations identified in Tables 3 and 3A represent “histaminebase” concentrations (e.g., the amount of histamine itself). Forexample, in the case of histamine phosphate, two molecules of phosphoricacid are attached to each molecule of histamine. Since the molecularweight of histamine phosphate is 307.15 and that of histamine itself is111.15, 2.75 mg of the salt are required to obtain 1 mg of activeprinciple. The administration dates are identified as an example only.Additionally, within a segment, the administration sequence can bevaried (e.g., rather than administration of C1, C2, C3 and C4,administration could be, for example C3, C3, C2 and C1) to any desiredorder depending on the embodiment. Further, in some embodiments, any one(or more) of segments 4, 5, 6, 7 or 8 in Table 3 or Table 3A can beinserted within any or all of segments 1, 2 and 3 (e.g., segment 4 is“nested” into segment 1)

In several embodiments, there are also provided “escalating” dosingregimens that are used to facilitate returning a patient's histamineconcentrations to within optimum ranges. The method comprises, inseveral embodiments, administering histamine (synthetic or natural), ahistamine agonist or antagonist, or a pharmaceutically acceptable saltthereof to the patient according to the non-limiting escalating dosingregimen shown in Table 4. In several embodiments, the escalating dosingregimen enables the increase of histamine levels in a patient having ahistamine level below a level required for optimum histamine function(e.g., treatment of histapenia). In several embodiments, the escalatingdosing regimen enables the decrease of histamine levels in a patienthaving histamine levels above those required for optimum histaminefunction (e.g., histadelia). As discussed herein, in severalembodiments, the method comprises administration of histamine (syntheticor natural), a histamine agonist or antagonist, or a pharmaceuticallyacceptable salt thereof to the subject.

In several embodiments, the escalating dosing regimen comprises aplurality (e.g., 2, 3, 4, 5, 6, or more) of segments, each comprising,for example, a plurality of individual doses. In several embodiments,the concentration of each dose within a segment is increased withrespect to the prior dose, but the volume administered is held constantacross a given dosing segment while all doses are administered with ashort amount of time (e.g. 5 minutes). Advantageously, shouldindividuals have sensitivity to histamine, in several embodiments,dosing regimens, such as the non-limiting embodiment of the dosingregimen shown in Table 4, are directed to only a portion of thehistamine receptors. For example, the non-limiting embodiment of thedosing regimen can be directed to the H1, H2 and H3 receptors (thoughadditional embodiments, however, comprise adjusted concentrations and/orvolumes to enable targeting of the H4 receptor in addition to the H1,H2, and/or H3 receptors). Additionally, in some embodiments, dosingregimens target only two histamine receptors. In such embodiments, thevolumes and concentrations are adjusted accordingly. For example, thenon-limiting example dosing regimen in Table 4 could be adjusted totarget H1 and H2 receptors or H2 and H4 receptors. In severalembodiments, the volumes are adjusted proportionately, such that, forexample, even with fewer doses (since only targeting 2 receptors), thetotal volume administered would remain as shown in Table 4.

In several embodiments, the escalating dosing regimen comprises segmentshaving 3 individual doses per segment (see e.g., the non-limitingembodiment in Table 4A). In several embodiments, concentration 1 (C2)has been eliminated from the segments. As discussed above, in someembodiments both C1 and C2 target the H3 and/or H4 receptors. Thus, theelimination of the C1 dose, in several embodiments, prevents orotherwise reduces risk of the subject developing refractoriness tohistamine and helps maintain the expression of the receptors at levelsthat promote proper histamine balance. Moreover, as the use of a singledose targeting the H3 and/or H4 receptors reduces risk of adverse sideeffects or sensitivity to histamine (or an agonist or antagonistthereof, depending on the embodiment), the escalating regimen does notemploy a “loading period”. Thus, the escalating dose regimen may beparticularly suited to individuals with a known elevated histaminetolerance (e.g., the elimination of the loading period and eliminationof the C1 dose is unlikely to induce adverse responses). Advantageously,should individuals have sensitivity to histamine, in severalembodiments, dosing regimens, such as the non-limiting embodiment of thedosing regimen shown in Table 4A, are directed to only a portion of thehistamine receptors. For example, the non-limiting embodiment of thedosing regimen shown in Table 4A is directed to the H1, H2 and H3receptors (though additional embodiments, however, comprise adjustedconcentrations and/or volumes to enable targeting of the H4 receptor inaddition to the H1, H2, and/or H3 receptors). Additionally, in someembodiments, dosing regimens target only two histamine receptors. Insuch embodiments, the volumes and concentrations are adjustedaccordingly. For example, the non-limiting example dosing regimen inTable 4A could be adjusted to target H1 and H2 receptors. In severalembodiments, the volumes are adjusted proportionately, such that, forexample, even with fewer doses (since only targeting 2 receptors), thetotal volume administered would remain as shown in Table 4A.

As discussed above, while the doses are administered separately, theycan be considered a single “dose” because the entirety of a segment isadministered on a reduced time frame (e.g., within about 5 seconds,within about 10 seconds, within about 15 seconds, etc.). Additionally,as the segment number increases, the duration between segmentsincreases, and as such the actual administration of histamine (or itsagonist or antagonist) occurs within a very short relative period oftime, thereby facilitating compliance of the subject and continuedmaintenance of the dosing regimens.

TABLE 4 “Escalating” Dosing Regimen for Histadelia and/or HistapeniaSegment Dose Concen- Administration Dosing Number Number tration VolumeDate Frequency 1 1 C1 0.05 mL January 6 2 weeks C2 0.05 mL (+/−1 C3 0.05mL week) C4 0.05 mL 2 2 C1 0.1 mL January 20 3 week  C2 0.1 mL (+/−1.5C3 0.1 mL weeks) C4 0.1 mL 3 3 C1 0.15 mL February 10 4 weeks C2 0.15 mL(+/−2 C3 0.15 mL weeks) C4 0.15 mL 4 4 C1 0.2 mL March 10 6 weeks C2 0.2mL (+/−3 C3 0.2 mL weeks) C4 0.2 mL 5 5 C1 0.25 mL April 21 8 weeks C20.25 mL (+/−4 C3 0.25 mL weeks) C4 0.25 mL 6 6 C1 0.3 mL June 16 10weeks  C2 0.3 mL (+/−5 C3 0.3 mL weeks) C4 0.3 mL C1 = 1.1 ng/mL +/− 30%histamine base C2 = 3 ng/mL +/− 50% histamine base C3 = 1.1 μg/mL +/−30% histamine base C4 = 3.33 μg/mL +/− 30% histamine base

TABLE 4A “Escalating” Dosing Regimen for Histadelia and/or HistapeniaSegment Dose Concentration/ Administration Dosing Number Number VolumeDate Frequency 1 1 C2/0.03 mL January 6 C3/0.03 mL C4/0.03 mL 2 2C2/0.07 mL January 13 1 week  C3/0.07 mL C4/0.07 mL 3 3  C2/0.1 mLJanuary 27 2 weeks  C3/0.1 mL  C4/0.1 mL 4 4 C2/0.13 mL February 17 3weeks C3/0.13 mL C4/0.13 mL 5 5 C2/0.17 mL March 17 4 weeks C3/0.17 mLC4/0.17 mL 6 6  C2/0.2 mL April 21 5 weeks  C3/0.2 mL  C4/0.2 mL 7 7C2/0.23 mL June 2 6 weeks C3/0.23 mL C4/0.23 mL 8 8 C2/0.27 mL July 21 7weeks C3/0.27 mL C4/0.27 mL 9 9 C2/0.33 mL September 15 8 weeks  C3/0.3mL  C4/0.3 mL 10 10 C2/0.33 mL November 17 9 weeks C3/0.33 mL C4/0.33 mLC1 = 1.0 pg/mL histamine base C2 = 1.0 ng/mL histamine base C3 = 1.0μg/mL histamine base C4 = 3.5 μg/mL histamine base

The concentrations identified in Table 4 and Table 4A represent“histamine base” concentrations (e.g., the amount of histamine itself).For example, in the case of histamine phosphate, two molecules ofphosphoric acid are attached to each molecule of histamine. Since themolecular weight of histamine phosphate is 307.15 and that of histamineitself is 111.15, 2.75 mg of the salt are required to obtain 1 mg ofactive principle. As with other tables, the dates provides on the tableare for guidance only (e.g., to represent time intervals as opposed toactual dates). Additionally, within a segment, the administrationsequence can be varied (e.g., rather than administration of C1, C2, C3and C4, administration could be, for example C3, C3, C2 and C1) to anydesired order depending on the embodiment.

There is provided, in several embodiments of the invention, a histaminereceptor activator (e.g., histamine) for use in the treatment ofpatients showing an elevated amount of circulating histamine or inpatients showing a reduced amount of circulating histamine, suchpatients being afflicted with migraine headaches, Parkinson's Disease,Alzheimer's Disease, coronary disease, leukemia, amyotrophic lateralsclerosis, epilepsy, histadelia and/or histapenia. Also provided is ahistamine receptor activator for use in the treatment of migraineheadaches, Parkinson's Disease, Alzheimer's Disease, coronary disease,leukemia, amyotrophic lateral sclerosis, epilepsy, histadelia and/orhistapenia with associated restoration of histamine balance. Someembodiments of the invention comprise a histamine receptor activator foruse in the treatment of diseases associated with the over-expressionand/or over-activity of the histamine H1 receptor and/or for use in thetreatment of diseases associated with the under-expression and/orunder-activity one or more of the histamine H2, H3, and/or H4 receptors.

As discussed above, the treatment according to the methods disclosedherein may be based on clinical assessment that a patient is sufferingfrom histapenia or histadelia, such as by a diagnostic assay indicatingthe presence of histamine levels above or below standard plasmahistamine levels or standard urine histamine levels. For example,histamine levels in the range of 45 to about 50 ng/ml of plasma are usedas an indicator for optimum histamine function in some embodiments, andplasma levels above or below this range indicate that the patient maybenefit from the methods disclosed herein.

Dietary supplements are also optionally used, in several embodiments tofacilitate rebalance of histamine. For example, in several embodiments,supplements that help promote methylation of histamine (e.g., tofacilitate metabolism of histamine) are optionally used to supplementcertain of the methods disclosed herein for treating histadelia).Methylation-promoting supplements include, but are not limited to,S-adenosylmethionine (SAM-e), methyl-B12, and trimethylglycine (TMG),dimethylglycine (DMG), or combinations thereof. Additionally, calcium(which helps mobilize histamine into the bloodstream) and/or vitamin C(which facilitates excretion of histamine) supplements can be used tohelp reduce histamine, in conjunction with the dosing regimens disclosedherein. Magnesium supplementation is used, in several embodiments, tofacilitate stabilization of mast cells (thereby reducing degranulationand histamine release). Low-histamine diets are also used in certainembodiments wherein a reduction in histamine is desired. Also, copper isassociated with the enzymes that degrade histamine, thus, in severalembodiments, reduction in dietary copper intake is beneficial intreating histapenia.

Histamine Compositions and Administration

In several embodiments, histamine is administered as a pharmaceuticallyacceptable salt. In several embodiments, the diphosphate (H₃PO₄) salt ofhistamine is employed. In several embodiments, histamine phosphate isused. Other salts may also be used, including but not limited to, acidaddition salts formed with inorganic acids such as hydrochloric acid(e.g., histamine dihydrochloride), hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid, and the like, or with organic acids suchas acetic acid, propionic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2,-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid p-chlorobenzenesulfonic acid, 2-naphthalenesulfonicacid, p-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like, as well as combinationsthereof.

In addition, in several embodiments, pharmaceutically acceptable saltsof histamine can be formed when an acidic proton present is capable ofreacting with inorganic or organic bases. Acceptable inorganic basesinclude, but are not limited to, sodium hydroxide, sodium carbonate,potassium hydroxide, aluminum hydroxide and calcium hydroxide.Acceptable organic bases include, but are not limited to, ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

As used, herein the term “pharmaceutically acceptable” shall be givenits ordinary meaning and shall also include components, compounds,chemicals, etc. useful in the preparation of a pharmaceuticalcomposition that is generally safe, non-toxic and neither biologicallynor otherwise undesirable and includes that which is acceptable forveterinary use as well as human pharmaceutical use. As used, herein, theterm “pharmaceutically acceptable salts” shall be given its ordinarymeaning and shall include salts of compounds that are pharmaceuticallyacceptable, as defined above, and/or that possess the desiredpharmacological activity.

In several embodiments, the methods employ a comprise administration ofone or more agonist and/or antagonist compounds. Depending on theembodiments the agonist or antagonist may be administered in order toincrease or decrease the function of a particular histamine receptor.For example, in several embodiments an H3R agonist may be administered,while in some embodiments, an H1R antagonist is administered. Theagonists may be superagonists, full agonists, partial agonists, orinverse agonists. Antagonists, depending on the embodiment, can becompetitive, non-competitive, uncompetitive, or silent antagonists. Theagonists and antagonists can also be either selective or non-selective,depending on the embodiment. In several embodiments, the use of one ormore agonist or antagonist compounds is in addition to use of anthertherapeutic agent (e.g., histamine).

In several embodiments, the methods optionally comprise administrationof an antihistamine compound. For example, in several embodiments anantagonist of the H1 receptor is administered in conjunction with thehistamine dosing regimen, and the reduction of H1 receptor activity bythe antagonist further potentiates the suppressive effects of the H2/H3receptors. For example, H1 antagonists that may be used include, but arenot limited to aceprometazine, acrivastine, alcaftadine, alimemazine,antazoline, aptazapine, astemizole, azatadine, azelastine, bamipine,bepotastine, bilastine, bisulepine, bromazine, brompheniramine,carbinoxamine, carbinoxamine/pseudoephedrine, cetirizine,chlorcyclizine, chloropyramine, chlorothen, chlorphenamine,chlorphenoxamine, cinnarizine, clemastine, clemizole, clobenzepam,clobenztropine, clocinizine, cyanodothiepin, cyclizine, cyproheptadine,dacemazine, deptropine, desloratadine, dexbrompheniramine,dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine,diphenylpyraline, doxylamine, drixoral, ebastine, embramine, emedastine,epinastine, esmirtazapine, etymemazine, fexofenadine, histapyrrodine,homochlorcyclizine, hydroxyethylpromethazine, hydroxyzine, hydroxyzine,isopromethazine, isothipendyl, ketotifen, latrepirdine, levocabastine,levocetirizine, loratadine, mebhydrolin, mepyramine, methafurylene,methapyrilene, methdilazine, 4-methyldiphenhydramine, mianserin,mirtazapine, mizolastine, moxastine, olopatadine, orphenadrine,oxatomide, pemirolast, phenindamine, pheniramine, phenyltoloxamine,pirolate, promethazine, propiomazine, pseudoephedrine/loratadine,pyrrobutamine, repirinast, resporal, rupatadine, setastine, setiptiline,talastine, terfenadine, thenalidine, thenyldiamine, thiazinamiummetilsulfate, thonzylamine, tolpropamine, toplexil, tripelennamine,triprolidine, and combinations thereof. In other embodiments, agonistcompounds may be used (e.g., depending on whether a subject is affectedwith histapenia or histadelia). In some embodiments, H1 agonists may beused, such as for example, when treating a subject with histapenia.Suitable H1 agonists include, but are not limited to 2-Pyridylethylaminedihydrochloride, Histamine trifluoromethyl toluidide, as well as thevarious salts of histamine (either synthetic or naturally occurring)disclosed herein, or combinations thereof.

In several embodiments, agonists of the H2R are used, including, but notlimited to, for example, arpromidine, amthamine, impromidine, dimaprit,sopromidine, 4-methylhistamine, and combinations thereof. Also, inseveral embodiments, H2R antagonists are used, including, but notlimited to, for example, cimetidine, mifentidine, nizatidine,ranitidine, titotidine, famotidine, zolantidine, iodoaminopotentidine,compound SKF 92857, mepyramine, loxtidine, and combinations thereof

H3 receptor agonists are used in several embodiments. Suitable H3Ragonists include, but are not limited to (R)-α-methylhistamine,cipralisant, immepip, imetit, immethridine, methimepip, proxyfan, andcombinations thereof. Conversely, H3R antagonists may be used, dependingon the embodiment. Suitable H3R antagonists include, but are not limitedto A-349,821, ABT-239, betahistine, burimamide, ciproxifan, conessine,clobenpropit, impentamine, iodophenpropit, thioperamide, VUF-5681(4-[3-(1H-Imidazol-4-yl)propyl]piperidine), and combinations thereof.

H4 receptor agonists are used in several embodiments. Suitable H4Ragonists include, but are not limited to VUF-8430(2-[(aminoiminomethyl)amino]ethyl carbamimidothioic acid ester), OUP-16,4-methylhistamine, and the various salts of histamine (either syntheticor naturally occurring) disclosed herein, or combinations thereof. H4Rantagonists may be used, depending on the embodiment. Suitable H4Rantagonists include, but are not limited to thioperamide, JNJ 7777120,VUF-6002(1-[(5-chloro-1H-benzimidazol-2-yl)carbonyl]-4-methylpiperazine),A987306, A943931, and combinations thereof.

In several embodiments, the invention comprises a histamine receptoractivator for use in the treatment of migraine headaches, Parkinson'sDisease, Alzheimer's Disease, coronary disease, leukemia, amyotrophiclateral sclerosis, epilepsy, histadelia and/or histapenia by inhibitingthe activity and/or expression of a histamine receptor selected from thegroup consisting of the histamine H1 receptor, the histamine H2receptor, the histamine H3 receptor, and the histamine H4 receptor. Inseveral embodiments, the histamine receptor activator inhibits theactivity and/or expression of the histamine H1 receptor and thus isbeneficial for use in the treatment of diseases associated with theover-expression and/or over-activity of the histamine H1 receptor.Moreover, in several embodiments, the histamine receptor activator (oractivators) are for use in the treatment of diseases associated with theunder-expression and/or under-activity one or more of the histamine H2,H3, and/or H4 receptors.

In several embodiments, the invention comprises a histamine receptoractivator for use in the treatment of migraine headaches, Parkinson'sDisease, Alzheimer's Disease, coronary disease, leukemia, amyotrophiclateral sclerosis, epilepsy, histadelia and/or histapenia by combined,sequential, or separate administration with a complete or partialantagonist of a histamine H1 receptor. Moreover, in several embodiments,the invention comprises an inhibitor of the activity and/or expressionof a histamine H1 receptor for use in the treatment of migraineheadaches, Parkinson's Disease, Alzheimer's Disease, coronary disease,leukemia, amyotrophic lateral sclerosis and/or epilepsy.

Depending on the embodiment, the histamine compositions used in themethods disclosed herein can be used in one or more of a variety offorms, depending on the route of administration. Administration can be,for example oral, ophthalmic, otologic, and/or nasal, urogenital,rectal, transdermal, via implantation, transdermal, inhalation and/orvia infusion. Patches may be used in one embodiment. Oral delivery canbe, for example, enteral (e.g., to the digestive tract), buccal (e.g.,sublingual), and/or inhaled (e.g., to the respiratory tract). Dependingon the embodiment, oral forms include, but are not limited to liquid,solid, and/or semi-solid forms. In several embodiments, enteraladministration is by way of administration of one or more of pills,tablets, capsules, gel-caps, (including timed release forms) osmoticdelivery systems, elixirs, suspension, syrup, emulsions, hydrogels,wafer, molecular encapsulation forms, softgels, solution, suspensions,syrups, tinctures, and/or tisanes. Buccal administration, in severalembodiments, is by way of administration of one or more of orallydisintegrating tablets or pills, films, lozenges, chewing gums,popsicles, lollipops, mouthwashes, mouth rinses, toothpaste, ointment,and/or oral sprays.

In several embodiments, oral forms may include one or more inert diluentand/or an edible carrier. For example, the compositions may be enclosedin gelatin capsules (for oral use) or compressed into tablets (for oralor buccal use) or formulated into troches or sublingual liquids (forbuccal use). In several embodiments, the active histamine compound canbe incorporated with excipients and and/or various pharmaceuticallycompatible carriers, binding agents, and/or adjuvant materials. Oralforms, may, depending on the embodiment, contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid, orcorn starch; a lubricant such as magnesium stearate; a gliding such ascolloidal silicon dioxide; a sweetening agent such as sucrose orsaccharin; or a flavoring agent or agents such as mint, methylsalicylate, or fruit flavors, candy flavors, combinations of flavors,etc. When the dosage unit form is a capsule, it can optionally contain,in addition to material of the above type, a liquid carrier such as afatty oil. In addition, dosage unit forms can contain various othermaterials which modify the physical form of the dosage unit, forexample, coatings of sugar, shellac, or other enteric agents.Administration to the respiratory tract, in several embodiments, is byway of administration of one or more of a dry powder inhaler, nebulize,vaporizer, metered dose-inhaler, respiratory mask, oxygen concentrator,nasal cannula, and the like.

Ophthalmic, otologic, and/or nasal administration are used in severalembodiments, and in some such embodiments are advantageous because ofthe rapid absorption of the histamine compositions through, for example,the mucous membranes. Forms for delivery via the eye, nose, or earinclude, but are not limited to, for example, nasal spray, ear drops,eye drops, ointments, hydrogels, nanosphere suspensions or emulsions,mucoadhesive microdisc (e.g., microsphere tablets) and the like.

Urogenital and/or rectal administration forms include, but are notlimited to ointments, pessary (e.g., vaginal suppository), vaginalrings, vaginal douches, intrauterine devices (IUD), extra-amnioticinfusions, intravesical infusions, suppositories, enema, and/or Murphydrip, etc.

Dermal administration forms, depending on the embodiment, include, butare not limited to ointments, liniments, pastes, films, hydrogels,liposomes, transfersome vesicles, creams, lotion, balms, salves,shampoos, dermal patches (e.g., transdermal patch), transdermal spray,direct or jet injector, etc.

Injection or infusion may also be used, depending on the embodiment. Forexample, delivery of histamine can be intradermal, subcutaneous, via atransdermal implant, intravenous, intramuscular, intraperitoneal,intraarterial, intracavernous, intracerebral, intrathecal, epidural, andthe like.

In several embodiments, the therapeutic agent is self-administered. Insome embodiments, the therapeutic agent is administered to a subject inneed thereof by a non-medical professional (an individual who is not amedical professional, such as for example, an acquaintance, familymember, spouse, etc.).

Combinations of the various administration routes are also used, inseveral embodiments. For example, an oral medication can be used inconjunction with a subcutaneous administration. Likewise, bothintramuscular and subcutaneous administration routes are optionallyemployed, for example. Solutions or suspensions used for injection orinfusion can optionally include one or more of the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerin, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid (EDTA); bufferssuch as acetates, citrates or phosphates and agents for the adjustmentof tonicity such as sodium chloride, mannitol and dextrose. Depending onthe embodiments, an injectable preparation can optionally be enclosed inampoules, disposable syringes or multiple dose vials made of glass orplastic, or other suitable material. When used in conjunction withhistamine compositions as disclosed herein, anti-histamines may also bein any of the above forms.

Concentrations and dosages provided in the examples below and the tablesabove are for a subject weight of 75-85 kg and can be adjustedproportionally for different weights according to several embodiments.In several embodiments, kits comprising pre-filled syringes, vials orother containers are provided with the doses of therapeutic agentdescribed herein. Instructions for use, including for example a paper orelectronic calendar system or other alert for scheduling self-treatment,are provided in one embodiment.

EXAMPLES

The examples provided herein are non-limiting examples of someembodiments of the invention.

Example 1—Histamine Dosing Regimen for Treatment of NeurologicalDisorders

In several embodiments, a histamine dosing regimen according to themethods disclosed above is used for the reduction and/or prevention ofneurological disorders, including migraine headaches, Parkinson's andAlzheimer's and ALS and epilepsy. A long-term migraine sufferer wastreated with the regimen shown in Table 5 (administration datesidentified as an example only). Histamine was administeredsubcutaneously according to the indicated times and concentrations.

Another possible regimen in accordance with several embodiments is shownin Table 5A (administration dates identified as an example only).

The concentrations identified in Table 5 and Table 5A represent“histamine base” concentrations (e.g., the amount of histamine itself).For example, in the case of histamine phosphate, two molecules ofphosphoric acid are attached to each molecule of histamine. Since themolecular weight of histamine phosphate is 307.15 and that of histamineitself is 111.15, 2.75 mg of the salt are required to obtain 1 mg ofactive principle. Additionally, within a segment, the administrationsequence can be varied (e.g., rather than administration of C1, C2, C3and C4, administration could be, for example C3, C3, C2 and C1) to anydesired order depending on the embodiment.

As a result of the histamine dosing regimen above, the subject (amigraine suffer for over 35 years) experienced a significant reductionin frequency of migraine episodes, as well as a reduction in intensityof migraines when they did occur. Prior to the dosing regimen, thesubject experienced about 3-5 migraines per week, on average. Thisfrequency was despite the use of various prescription drugs, over thecounter drugs, dietary changes, and/or alternative medicine approaches.Migraine events resulted in numerous missed work days, and reduced workefficiency. Migraines also caused loss of certain occupationalpromotional opportunities and, outside of work, loss of the ability toexercise (as physical exertion triggered migraine attacks). Overall themigraine events led to a consistent decline in quality of life.

As a result of implementing the above mentioned histamine dosingregimen, the intensity and frequency of migraines has been drasticallyreduced in this subject, who currently experiences approximately only 1migraine every 2 months. Drastically improved quality of life hasresulted, as has the subject's ability to spend interactive time withthe subject's family, being able to participate in family and socialevents, being able to exercise and becoming a productive member ofsociety. This regimen also resulted in limited side effects associatedwith the regimen (e.g., no histamine-induced headaches). After segment 5was completed, the subject restarted the dosing regimen at segment 1after a period of time had elapsed. As discussed above, the prevalenceof histamine in various physiological functions, and histamine imbalancein a variety of diseases and/or disorders make several embodiments ofthe invention useful for treatment of other diseases and/or disordersincluding, but not limited to Parkinson's disease, Alzheimer's disease,epilepsy, ALS, and other disorders disclosed herein. In someembodiments, one or more segment durations may be compressed or expandedby e.g., 50% to 99% (e.g., 60%, 75%, 85%, 90%, 95%).

Example 2—Extended Histamine Dosing Regimen for Treatment

In several embodiments, an extended histamine dosing regimen is used forthe reduction and/or prevention of neurological disorders, includingmigraine headaches, Parkinson's and Alzheimer's, coronary disease,leukemia, ALS, epilepsy, histadelia and/or histapenia (among others).

The concentrations identified in Table 6 represent “histamine base”concentrations (e.g., the amount of histamine itself). For example, inthe case of histamine phosphate, two molecules of phosphoric acid areattached to each molecule of histamine. Since the molecular weight ofhistamine phosphate is 307.15 and that of histamine itself is 111.15,2.75 mg of the salt are required to obtain 1 mg of active principle. Insome embodiments, one or more segment durations may be compressed orexpanded by e.g., 50% to 99% (e.g., 60%, 75%, 85%, 90%, 95%). Otherhistamine compounds may be used instead of or in addition to histaminephosphate. Additionally, within a segment, the administration sequencecan be varied (e.g., rather than administration of C1, C2, C3 and C4,administration could be, for example C3, C3, C2 and C1) to any desiredorder depending on the embodiment.

Example 3—Extended Histamine Dosing Regimen

In several embodiments, an extended histamine dosing regimen is used forthe reduction and/or prevention of neurological disorders, includingmigraine headaches, Parkinson's and Alzheimer's, ALS epilepsy,histadelia and/or histapenia, among others.

The concentrations identified in Table 7 represent “histamine base”concentrations (e.g., the amount of histamine itself). For example, inthe case of histamine phosphate, two molecules of phosphoric acid areattached to each molecule of histamine. Since the molecular weight ofhistamine phosphate is 307.15 and that of histamine itself is 111.15,2.75 mg of the salt are required to obtain 1 mg of active principle. Insome embodiments, one or more segment durations may be compressed orexpanded by e.g., 50% to 99% (e.g., 60%, 75%, 85%, 90%, 95%). Otherhistamine compounds may be used instead of or in addition to histaminephosphate. Additionally, within a segment, the administration sequencecan be varied (e.g., rather than administration of C1, C2, C3 and C4,administration could be, for example C3, C3, C2 and C1) to any desiredorder depending on the embodiment.

Example 4—Representative Formulation

A representative formulation for use in several embodiments of thehistamine dosing regimens disclosed herein is a formulation suitable forsubcutaneous injection comprising, histamine base 1 mg/mL (histaminephosphate 2.75 mg/mL) in glycerin 50% (v/v). As disclosed herein, otherhistamine receptor activators can be used instead of or in addition tohistamine phosphate. Moreover, other diluents/carriers can be usedinstead of, or in addition to glycerin (e.g., saline, sterile water,etc.).

Although the examples above and several embodiments discuss thehistamine system, the approaches described herein may be used torebalance other systems. For example, in some embodiments, therapeuticagents include agents that affect neurotransmission, such as agents thataffect one or more of the dopamine, noradrenaline, serotonin, GABA andacetylcholine systems. The targeted and controlled pattern of receptormodulation may be particularly effective for neurological disorders.Thus, agonists and antagonists of these neurotransmission pathways,according to the approaches described herein, are encompassed withinthis disclosure.

When the singular forms “a,” “an” and “the” or like terms are usedherein, they will be understood to include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “anagent” includes two or more agents, and the like. The word “or” or liketerms as used herein means any one member of a particular list and alsoincludes any combination of members of that list.

Throughout the description and claims of this specification, the word“comprise” and variations of the word, such as “comprising” and“comprises,” means “including but not limited to,” and is not intendedto exclude, for example, other additives, components, integers or steps.

It is contemplated that various combinations or subcombinations of thespecific features and aspects of the embodiments disclosed above may bemade and still fall within one or more of the inventions. Further, thedisclosure herein of any particular feature, aspect, method, property,characteristic, quality, attribute, element, or the like in connectionwith an embodiment can be used in all other embodiments set forthherein. Accordingly, it should be understood that various features andaspects of the disclosed embodiments can be combined with or substitutedfor one another in order to form varying modes of the disclosedinventions. Thus, it is intended that the scope of the presentinventions herein disclosed should not be limited by the particulardisclosed embodiments described above. Moreover, while the invention issusceptible to various modifications, and alternative forms, specificexamples thereof have been shown in the drawings and are hereindescribed in detail. It should be understood, however, that theinvention is not to be limited to the particular forms or methodsdisclosed, but to the contrary, the invention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the various embodiments described and the appended claims.Any methods disclosed herein need not be performed in the order recited.The methods disclosed herein include certain actions taken by apractitioner; however, they can also include any third-party instructionof those actions, either expressly or by implication. For example,actions such as “administering histamine” include “instructing theadministration of histamine.” The ranges disclosed herein also encompassany and all overlap, sub-ranges, and combinations thereof. Language suchas “up to,” “at least,” “greater than,” “less than,” “between,” and thelike includes the number recited. Numbers preceded by a term such as“about” or “approximately” include the recited numbers. For example,“about 3 mm” includes “3 mm.”

1. (canceled)
 2. A decreasing histamine dosing regimen comprising insequential order: a) a first dosing segment comprising two or moresequential doses of histamine separated by one or more equal timeintervals (the “first time interval”), wherein the doses decrease inhistamine concentration from dose to dose while the administered volumeof each dose stays constant; and b) a second dosing segment comprisingtwo or more sequential doses of histamine separated by one or more equaltime intervals (the “second time interval”), wherein the doses decreasein histamine concentration from dose to dose while the administeredvolume of each dose stays constant; wherein the volume of each histaminedose in the second dosing segment is greater than the volume of eachhistamine dose in the first dosing segment, and the second time intervalis longer than the first time interval.
 3. A histamine dosing regimencomprising in sequential order: a) a first dosing segment comprising twoor more sequential doses of histamine separated by one or more equaltime intervals (the “first time interval”), wherein the histamineconcentration varies from dose to dose while the administered volume ofeach dose decreases; and b) a second dosing segment comprising two ormore sequential doses of histamine separated by one or more equal timeintervals (the “second time interval”), wherein the histamineconcentration varies from dose to dose while the administered volume ofeach dose decreases; wherein the volume of each histamine dose in thesecond dosing segment is less than the volume of each histamine dose inthe first dosing segment, and the second time interval is longer thanthe first time interval.
 4. A histamine dosing regimen comprising insequential order: a) a first dosing segment comprising two or moresequential doses of histamine separated by one or more equal timeintervals (the “first time interval”), wherein the histamineconcentration varies from dose to dose while the administered volume ofeach dose remains constant; and b) a second dosing segment comprisingtwo or more sequential doses of histamine separated by one or more equaltime intervals (the “second time interval”), wherein the histamineconcentration varies from dose to dose while the administered volume ofeach dose remains constant; wherein the second time interval is longerthan the first time interval.